WO2023177689A1 - Régimes d'antagoniste de vegf à dose élevée et étendu pour le traitement de troubles oculaires angiogéniques - Google Patents

Régimes d'antagoniste de vegf à dose élevée et étendu pour le traitement de troubles oculaires angiogéniques Download PDF

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WO2023177689A1
WO2023177689A1 PCT/US2023/015223 US2023015223W WO2023177689A1 WO 2023177689 A1 WO2023177689 A1 WO 2023177689A1 US 2023015223 W US2023015223 W US 2023015223W WO 2023177689 A1 WO2023177689 A1 WO 2023177689A1
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fusion protein
vegf receptor
weeks
receptor fusion
dose
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PCT/US2023/015223
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Robert L. Vitti
Alyson J. BERLINER
Karen Chu
Friedrich Asmus
Sergio Casimiro DA SILVA LEAL
Thomas Eissing
Kay D. Rittenhouse
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Regeneron Pharmaceuticals, Inc.
Bayer Healthcare Llc
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Priority claimed from CA3190726A external-priority patent/CA3190726A1/fr
Application filed by Regeneron Pharmaceuticals, Inc., Bayer Healthcare Llc filed Critical Regeneron Pharmaceuticals, Inc.
Priority to AU2023234355A priority Critical patent/AU2023234355A1/en
Publication of WO2023177689A1 publication Critical patent/WO2023177689A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/179—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • the field of the present invention relates to methods for treating or preventing angiogenic eye disorders by administering a VEGF antagonist.
  • Diabetic retinopathy is the most common microvascular complication of diabetes.
  • Diabetic macular edema (DME), a manifestation of diabetic retinopathy, is the primary cause of vision loss and blindness in subjects with diabetes and the most frequent cause of blindness in young and middle-aged adults. If left untreated, approximately half of subjects with DME will lose 2 or more lines of visual acuity (VA) within 2 years.
  • VA visual acuity
  • CSME clinically significant macular edema ranges from 2.77% to 7.6%.
  • Treatment of DME is chronic and life-long in most subjects to suppress retinal edema and recurrences of choroidal neovascularization (CNV).
  • CNV choroidal neovascularization
  • the currently approved IVT anti-VEGF therapies are efficacious and well-tolerated, the need for IVT injections every 4 to 8 weeks, specifically in the initial phase and during maintenance of treatment, represents a significant burden to physicians, subjects, and caregivers.
  • VEGF antagonist therapeutic protein in the dosing formulation is a potential way to bring further benefits to subjects with chorioretinal vascular diseases, including DME.
  • a higher dose of aflibercept administered IVT has the potential to prolong the drug’s therapeutic effects.
  • the resulting extension of treatment intervals early after the initiation of treatment to every 12 weeks or 16 weeks would reduce the number of injections in the first treatment year.
  • a potential decrease in injection-related treatment burden and safety events with fewer injections could be a significant contribution to subject care and healthcare services.
  • EYLEA (2 mg dose, administered at a concentration of 40 mg/mL, also called intravitreal aflibercept injection [IAI]) is currently approved in the United States (US) for the treatment of nAMD, and is also approved for the treatment of macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME), and diabetic retinopathy (DR).
  • US United States
  • IAI intravitreal aflibercept injection
  • the present invention provides methods for treating or preventing diabetic retinopathy and/or diabetic macular edema comprising administering one or more doses (e.g., of >8 mg) of aflibercept such that the clearance of free aflibercept from the ocular compartment is about 0.367-0.458 mL/day (e.g., 0.41 mL/day) after an intravitreal injection of aflibercept and the time for the amount for free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after said intravitreal injection of aflibercept is about 15 weeks; and the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma (e.g., about 0.0156 mg/L) of a subject after said intravitreal injection of aflibercept is about 3.5 weeks; for example, wherein the aflibercept is administered in an aqueous pharmaceutical formulation wherein the afliber
  • the aqueous pharmaceutical formulation comprises an aqueous pharmaceutical formulation comprising: at least about 100 mg/ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3 of VEGFR2, and a multimerizing component; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.
  • a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3 of VEGFR2, and a multimerizing component; about 10-100 mM L
  • the method comprises administering a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or more tertiary doses of about 8 mg or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 (preferably 12, 16 or 20) weeks after the immediately preceding dose.
  • the present invention provides a method for slowing the clearance of free aflibercept from the ocular compartment after an intravitreal injection relative to the rate of clearance of aflibercept from the ocular compartment after an intravitreal injection of ⁇ _4 mg aflibercept comprising intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or more tertiary doses of about 8 mg or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks after the immediately preceding dose.
  • the clearance of free aflibercept from the ocular compartment is about 34% slower than that from the ocular compartment after an intravitreal injection of ⁇ 4 mg aflibercept, e.g., wherein the clearance of free aflibercept from the ocular compartment is about 0.367-0.458 mL/day or 0.41 mL/day after an intravitreal injection of > 8 mg aflibercept.
  • the present invention also provides a method for increasing the time for the amount of free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after an intravitreal injection of aflibercept relative to the time to reach LLOQ of the amount of free aflibercept in the ocular compartment of a subject after an intravitreal injection of about 2 mg aflibercept, e.g., increasing by greater than 1.3 weeks, for example, by about 6 weeks-to more than 10 weeks, for example, to about 15 weeks, comprising intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or more tertiary doses of about 8 mg or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each terti
  • the present invention also provides a method for increasing the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma (e.g., about 0.0156 mg/L) of a subject after an intravitreal injection of aflibercept relative to the time to reach LLOQ of free aflibercept in the plasma of a subject after an intravitreal injection of about 2 mg aflibercept, e.g., increased by more than 1.5 weeks, for example by about 2 weeks-to about 3.5 weeks, comprising intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or more tertiary doses of about 8 mg or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks
  • the >8 mg aflibercept is administered in an aqueous pharmaceutical formulation including aflibercept which includes one or more of histidine-based buffer, arginine (e.g., L-arginine, for example, L-arginine HCI), a sugar or polyol such as sucrose and having a pH of about 5.8.
  • arginine e.g., L-arginine, for example, L-arginine HCI
  • sucrose e.g., a sugar or polyol such as sucrose and having a pH of about 5.8.
  • the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C; for example, wherein the >8 mg aflibercept is in an aqueous pharmaceutical formulation comprising an aqueous pharmaceutical formulation comprising: at least about 100 mg/ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3 of VEGFR2, and a multimerizing component; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after
  • the present invention provides a method for treating or preventing diabetic retinopathy (DR) and/or diabetic macular edema (DME), in a subject in need thereof, for improving best corrected visual acuity (BCVA) in a subject in need thereof with DR and/or DME; or for promoting retinal drying in a subject with DR and/or DME in need thereof; comprising administering to an eye of the subject, one or more doses of about 8 mg or more of VEGF receptor fusion protein, preferably aflibercept, once every 12, 13, 14, 15, 16, 17, 18, 19 or 20 or 12-20 or 12-16 or 16-20 weeks.
  • DR diabetic retinopathy
  • DME diabetic macular edema
  • the method comprises [00014] administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks after the immediately preceding dose.
  • the present invention includes a method for treating or preventing diabetic retinopathy (DR) and/or diabetic macular edema (DME), in a subject in need thereof, comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks after the immediately preceding dose.
  • DR diabetic retinopathy
  • DME diabetic macular edema
  • the present invention also includes a method for treating or preventing diabetic retinopathy (DR) and/or diabetic macular edema (DME), in a subject in need thereof, comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 16 weeks after the immediately preceding dose.
  • DR diabetic retinopathy
  • DME diabetic macular edema
  • the present provides a method for treating or preventing diabetic retinopathy (DR) and/or diabetic macular edema (DME), in a subject in need thereof, comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 20 weeks after the immediately preceding dose.
  • DR diabetic retinopathy
  • DME diabetic macular edema
  • the method for treating or preventing DR and/or DME in a subject comprises comprising administering, to a subject in need thereof, 8 mg VEGF receptor fusion protein, preferably aflibercept, (0.07 ml_ or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by 8 mg VEGF receptor fusion protein (0.07 ml_) via intravitreal injection once every 8 - 16 weeks (2 - 4 months, +/- 7 days).
  • 8 mg VEGF receptor fusion protein preferably aflibercept
  • the method comprises administering 8 mg VEGF receptor fusion protein, preferably aflibercept, (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by 8 mg VEGF receptor fusion protein (0.07 mL) via intravitreal injection once every 12 weeks (2 - 4 months, +/- 7 days).
  • 8 mg VEGF receptor fusion protein preferably aflibercept
  • the method comprises administering 8 mg VEGF receptor fusion protein, preferably aflibercept, (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by 8 mg VEGF receptor fusion protein (0.07 mL) via intravitreal injection once every 16 weeks (2 - 4 months, +/- 7 days).
  • 8 mg VEGF receptor fusion protein preferably aflibercept
  • the method comprises administering 8 mg VEGF receptor fusion protein, preferably aflibercept, (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by 8 mg VEGF receptor fusion protein (0.07 mL) via intravitreal injection once every 20 weeks (+/- 7 days).
  • 8 mg VEGF receptor fusion protein preferably aflibercept
  • the present invention also provides a method for treating or preventing diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof: (1) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein, then the method comprises, after 1 month, administering to the subject the initial 8 mg dose of VEGF receptor fusion protein and, 1 month thereafter, the 1 st 8 mg secondary dose of VEGF receptor fusion protein; and, 1 month thereafter, the 2 nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen; (2) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein, then the method comprises, after 1 month, administering to the subject the first 8 mg secondary dose of VEGF receptor fusion protein and, 1 month thereafter, the 2 nd 8 mg secondary dose of VEGF receptor fusion
  • the method comprises, after 1 month, administering to the subject the 2 nd 8 mg secondary dose of VEGF receptor fusion protein and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the 1 st 8 mg maintenance dose of VEGF receptor fusion protein and all further 8 mg maintenance doses of VEGF receptor fusion protein every 12 or 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1 st 2 mg secondary dose of VEGF receptor fusion protein after 1 month, then the method comprises, after another 1 month, administering to the subject the initial 8
  • the method comprises, after another 1 month, administering to the subject the 1 st 8 mg maintenance dose of VEGF receptor fusion protein and all further 8 mg maintenance doses of VEGF receptor fusion protein every 12 or 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen; (9) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1 st 2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2 nd 2 mg secondary dose of VEGF receptor fusion protein after another 1 month, then the method comprises, after another 1 month, administering to the subject the initial 8 mg dose of VEGF receptor fusion protein and, 1 month thereafter, the 1 st 8 mg secondary dose of VEGF receptor fusion protein; and 1 month thereafter, the 2 nd 8 mg secondary dose of VEGF receptor
  • the present invention also provides a method for treating or preventing diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof who has been on a dosing regimen for treating or preventing said disorder wherein: (a) the subject has received an initial 8 mg dose of VEGF receptor fusion protein then the method comprises, after 1 month, administering to the subject the first 8 mg secondary dose of VEGF receptor fusion protein and 1 month thereafter, administering the 2 nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, administering one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen; or (b) the subject has received an initial 8 mg dose of VEGF receptor fusion protein & 1 st 8 mg secondary dose of VEGF receptor fusion protein after 1 month, then the method comprises, after another 1 month, administering to the subject the 2 nd 8 mg secondary dose of VEGF receptor fusion protein after
  • the present invention also provides a method for treating or preventing an angiogenic eye disorder (preferably DR and/or DME), in a subject in need thereof who has been on a dosing regimen for treating or preventing the disorder calling for a single initial dose of about 2 mg of VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 2 mg of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 2 mg of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose; and wherein the subject is at any phase of the 2 mg VEGF receptor fusion protein dosing regimen, comprising administering to an eye of the subject, an 8 mg dose of VEGF receptor fusion protein, evaluating the subject in about 8 or 10 or 12 weeks after said administering and, if, in the judgment of the treating physician dosing every 12
  • a subject in a method of the present invention has been on a dosing regimen for treating or preventing diabetic retinopathy and/or diabetic macular edema of a single initial dose of about 2 mg of a VEGF receptor fusion protein, preferably aflibercept, followed by 4 secondary doses of about 2 mg of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 2 mg of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose.
  • the present invention also provides a method for treating or preventing diabetic retinopathy or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 or 16 weeks after the immediately preceding dose; further comprising, after receiving one or more of said tertiary doses about 12 or 16 after the immediately preceding dose, lengthening the tertiary dose interval from 12 weeks to 16 weeks; 12 weeks to 20 weeks; or 16 weeks to 20 weeks, after the immediately preceding dose.
  • a single initial dose of about 8
  • the subject during said treatment, the subject exhibits (a) ⁇ 5 letter loss in BCVA; and/or (b) central retinal thickness (CRT) ⁇ 300 or 320 pm.
  • the method further comprises evaluating BVCA and/or CRT in the subject and, if the subject exhibits (a) ⁇ 5 letter loss in BCVA; and/or (b) CRT ⁇ 300 or 320 pm, lengthening the tertiary dose interval.
  • the present invention also provides a method treating or preventing diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject, a single initial dose of about >8 mg or more of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 or 16 or 20 weeks after the immediately preceding dose; further comprising, after receiving one or more of said tertiary doses about 12 or 16 or 20 weeks after the immediately preceding dose, shortening the tertiary dose interval from 12 weeks to 8 weeks; 16 weeks to 12 weeks; 16 weeks to 8 weeks, 20 weeks to 8 weeks, 20 weeks
  • the subject during said treatment, the subject exhibits (a) > 10 letter loss in BCVA relative to baseline; and/or (b) > 50 pm increase in CRT relative to baseline.
  • the method further comprises evaluating BVCA and/or CRT in the subject and, if the subject exhibits (a) > 10 letter loss in BCVA relative to baseline; and/or (b) > 50 pm increase in CRT relative to baseline, shortening the tertiary dose interval.
  • the present invention provides a method for treating or preventing diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject 3 doses of about 8 mg VEGF receptor fusion protein, preferably aflibercept, in a formulation that comprises about 114.3 mg/ml VEGF receptor fusion protein at an interval of once every 4 weeks; wherein after said 3 doses, administering one or more doses of the VEGF receptor fusion protein at an interval which is lengthened up to 12, 16 or 20 weeks.
  • VEGF receptor fusion protein preferably aflibercept
  • the present invention includes a method for treating or preventing diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of VEGF receptor fusion protein, preferably aflibercept, followed by 2 secondary doses of about 8 mg or more of the VEGF receptor fusion protein, wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and, after said doses, a) determining if the subject meets at least one criterion for reducing or lengthening one or more intervals by 2 weeks, 3 weeks, 4 weeks or 2-4 weeks between doses of the VEGF receptor fusion protein; and b) if said determination is made, administering further doses of the VEGF receptor fusion protein at said reduced or lengthened intervals between doses wherein criteria for lengthening the interval include: 1.
  • criteria for reducing the interval include: 1. >10 letter loss in BCVA; 2. persistent or worsening DME; and/or 3. >50 micrometers increase in CRT.
  • criteria for lengthening the interval include both: 1. ⁇ 5 letter loss in BCVA from week 12; and 2. CRT ⁇ 300 or 320 micrometers as measured by SD-OCT; and/or wherein criteria for reducing the interval include both: 1. >10 letter loss in BCVA, e.g., from week 12 in association with persistent or worsening DME; and 2. >50 micrometers increase in CRT, e.g., from week 12.
  • said criteria if said criteria are met, said interval is lengthened to 12, 16 or 20 weeks.
  • the present invention provides a method for treating or preventing diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof that has been pre-treated with one or more 2 mg doses of VEGF receptor fusion protein, preferably aflibercept, comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks after the immediately preceding dose.
  • VEGF receptor fusion protein preferably aflibercept
  • the present invention provides a method for treating or preventing an angiogenic eye disorder, preferably DR and/or DME, in a subject in need thereof, comprising administering to an eye of the subject, (1) a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose; or (2) one or more doses of 8 mg or more of VEGF receptor fusion protein about every 4 weeks.
  • subjects having certain exclusion criteria are excluded from treatment or are not excluded from treatment if exclusion criteria are not met.
  • a subject having any one or more of ocular or periocular infection; active intraocular inflammation; and/or hypersensitivity is excluded from administration of VEGF receptor fusion protein to the eye.
  • a method of the present invention further comprises a step of evaluating the subject for: ocular or periocular infection; active intraocular inflammation; and/or hypersensitivity; and excluding the subject from said administration if any one or more if found in the subject.
  • subjects are monitored for adverse events, such as conjunctival hemorrhage, cataract, vitreous detachment, vitreous floaters, corneal epithelium defect and/or increased intraocular pressure. If such AEs are identified, the identified AE may be treated and/or such treatment or prevention may be ceased.
  • adverse events such as conjunctival hemorrhage, cataract, vitreous detachment, vitreous floaters, corneal epithelium defect and/or increased intraocular pressure.
  • a method includes preparation prior to administration of a VEGF receptor fusion protein, preferably aflibercept.
  • the method comprises, prior to each administration, providing or having available- one singledose glass vial having a protective plastic cap and a stopper containing an aqueous formulation comprising 8 mg VEGF receptor fusion protein in about 70 microliters; a filter needle, e.g., one 18-gauge x 1 1 /2-inch, 5-micron, filter needle that includes a tip and a bevel; an invention needle, e.g., one 30-gauge x %-inch injection needle; and a syringe, e.g., one 1-mL Luer lock syringe having a graduation line marking for 70 microliters of volume; packaged together; then (1) visually inspecting the aqueous formulation in the vial and, if particulates, cloudiness, or discoloration are visible, then using another vial of aqueous formulation containing
  • injection of VEGF receptor fusion protein is performed under controlled aseptic conditions, which comprise surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) and anesthesia and a topical broadspectrum microbicide are administered prior to the injection.
  • controlled aseptic conditions comprise surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) and anesthesia and a topical broadspectrum microbicide are administered prior to the injection.
  • the subject has been receiving a dosing regimen for treating or preventing diabetic retinopathy and/or diabetic macular edema calling for: a single initial dose of about 2 mg of VEGF receptor fusion protein, followed by 4 secondary doses of about 2 mg of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 2 mg of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose; wherein the subject is at any phase (initial dose, secondary dose or tertiary dose) of the 2 mg VEGF receptor fusion protein dosing regimen.
  • one or more secondary doses is 2 secondary doses; 2 to 4 weeks is about 4 weeks; 12-20 weeks is about 12 weeks; 12-20 weeks is about 16 weeks; 12-20 weeks is about 20 weeks; 12-20 weeks is about 12-16 weeks; 8-16 weeks is about 12 weeks; 8-16 weeks is about 16 weeks; 8-16 weeks is about 12-16 weeks; 2 to 4 weeks is about 4 weeks and one or more secondary doses is 2 secondary doses; 12-20 weeks is about 12 weeks and one or more secondary doses is 2 secondary doses; 12-20 weeks is about 16 weeks and one or more secondary doses is 2 secondary doses; 12-20 weeks is about 20 weeks and one or more secondary doses is 2 secondary doses; 12-20 weeks is about 12-16 weeks and one or more secondary doses is 2 secondary doses; 2 to 4 weeks is about 4 weeks and one or more secondary doses is 2 secondary doses and the VEGF receptor fusion protein is aflibercept; 12-20 weeks is about 12 weeks and one or more secondary doses is 2 secondary doses and the VEGF receptor fusion protein is aflibercept; 12-20
  • the VEGF receptor fusion protein comprises amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO: 2; is selected from the group consisting of: aflibercept and conbercept; comprises two polypeptides that comprise (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO: 2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO: 2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO: 2; comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3 of a VEGFR2, and a multimerizing component; comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3 of VEGFR2, an Ig domain 4 of VEGFR2 and a multimerizing component; or comprises two VEGFR1 R2-FcAC1(a
  • the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation selected from the group consisting of A-KKKK. In an embodiment of the invention, the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising about 114.3 mg/ml VEGF receptor fusion protein, preferably aflibercept.
  • the VEGF receptor fusion protein is administered to both eyes of the subject.
  • the VEGF receptor fusion protein preferably aflibercept
  • a subject has previously received one or more doses of 2 mg VEGF receptor fusion protein, e.g., Eylea.
  • One or more further doses than specifically mentioned may be administered to a subject.
  • a subject who has received 2 mg of VEGF receptor fusion protein preferably aflibercept, has received the protein in an aqueous pharmaceutical formulation comprising 40 mg/ml VEGF receptor fusion protein, 10 mM sodium phosphate, 40 mM NaCI, 0.03% polysorbate 20 and 5% sucrose, with a pH of 6.2.
  • the 8 mg VEGF receptor fusion protein is in an aqueous pharmaceutical formulation including >100 mg/ml VEGF receptor fusion protein, histidine-based buffer and arginine (preferably L-arginine); e.g., comprising a sugar or polyol (e.g., sucrose).
  • the formulation has a pH of about 5.8.
  • the formulation may include about 103-126 mg/ml of the VEGF receptor fusion protein, histidine-based buffer and arginine; in an embodiment of the invention, including about 114.3 mg/ml of the VEGF receptor fusion protein, histidine-based buffer and arginine.
  • the 8 mg of VEGF receptor fusion protein is administered in a volume of about 100 pl or less, about 75 pl or less; about 70 pl or less; or about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl; 78 pl; 79 pl;
  • the methods herein include the step of administering the VEGF receptor fusion protein, preferably aflibercept, to both eyes of the subject, e.g., intravitreally.
  • the VEGF receptor fusion protein preferably aflibercept
  • the subject achieves and/or maintains one or more of, an improvement in Diabetic Retinopathy Severity Scale (DRSS); an improvement in best corrected visual acuity; a dry retina; a gain in best corrected visual acuity; a BCVA of at least 69 letters; a foveal center without fluid; a decrease in central retinal thickness (CRT); no vascular leakage as measured by fluorescein angiography (FA); an improvement from pre-treatment baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ) total score; a retina without fluid (total fluid, intraretinal fluid [IRF] and/or subretinal fluid [SRF]) at the foveal center and in center subfield; maintenance of a fluid-free retina (total fluid, I RF and/or SRF at foveal center and in the center subfield); a lack of macular edema; a retina free of fluid on spectral domain optical coherence tomography (DRSS); an improvement in best corrected visual
  • a dry retina lacks intraretinal fluid and/or subretinal fluid; or retinal drying is characterized by no intraretinal fluid (IRF) and no subretinal fluid (SRF) in the eye of the subject, after the subject has received three monthly doses of the VEGF receptor fusion protein, preferably aflibercept.
  • IRF intraretinal fluid
  • SRF subretinal fluid
  • reference to 4 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56 or 60 weeks from start of treatment is about 48 weeks or 60 weeks from start of treatment.
  • 1 initial dose, 2 secondary doses and 3 tertiary doses of VEGF receptor fusion protein, e.g., aflibercept are administered to the subject in the first year; 1 initial dose, 2 secondary doses and 2 tertiary doses of VEGF receptor fusion protein, e.g., aflibercept, are administered to the subject in the first year; or 1 initial dose, 2 secondary doses and 3 tertiary doses of VEGF receptor fusion protein, e.g., aflibercept, are administered to the subject in the first year followed by 2 -4 tertiary doses in the second year.
  • the interval between doses are adjusted (increased/maintained/reduced) based on visual and/or anatomic outcomes, e.g., according to criteria as set forth in Figure 3 and/or Figure 4.
  • the present invention also provides a kit comprising a container comprising VEGF receptor fusion protein; and Instruction for use of VEGF receptor fusion protein, wherein the container is a vial or a pre-filled syringe, wherein the container comprises > 100 mg/mL VEGF receptor fusion protein, wherein the container comprises > 114.3 mg/mL VEGF receptor fusion protein, wherein the instruction comprises instruction for the administration of aflibercept to DME/AMD patients, wherein the instruction comprises instruction that aflibercept 8 mg treatment is initiated with 1 injection per month (every 4 weeks) for 3 consecutive doses, wherein the instruction comprises instruction that after the initial 3 consecutive doses the injection interval may be lengthened up to every 16 week or every 20 week, and wherein the instruction comprises instruction that the treatment interval may be adjusted based on the physician’s judgement of visual and/or anatomic outcomes.
  • the present invention provides aflibercept for use in the treatment or prevention of diabetic retinopathy and/or diabetic macular edema in a subject in need thereof comprising administering one or more doses of aflibercept at an interval and quantity whereby the clearance of free aflibercept from the ocular compartment is about 0.367-0.458 mL/day after an intravitreal injection of aflibercept, the time for the amount for free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after said intravitreal injection of aflibercept is about 15 weeks; and the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma of the subject after said intravitreal injection of aflibercept is about 3.5 weeks.
  • LLOQ lower limit of quantitation
  • the present invention provides aflibercept for use in a method for slowing the clearance of free aflibercept from the ocular compartment after an intravitreal injection relative to the rate of clearance of aflibercept from the ocular compartment after an intravitreal injection of ⁇ 4 mg aflibercept
  • the method comprises intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or more tertiary doses of about 8 mg or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks after the immediately preceding dose.
  • the present invention provides aflibercept for use a method for increasing the time for the amount of free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after an intravitreal injection of aflibercept relative to the time to reach LLOQ of the amount of free aflibercept in the ocular compartment of a subject after an intravitreal injection of about 2 mg aflibercept, wherein the method comprises intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or more tertiary doses of about 8 mg or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks after the immediately preceding dose.
  • LLOQ lower limit of quantitation
  • the present invention provides aflibercept for use in a method for increasing the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma of a subject after an intravitreal injection of aflibercept relative to the time to reach LLOQ of free aflibercept in the plasma of a subject after an intravitreal injection of about 2 mg aflibercept, wherein the method comprises intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or more tertiary doses of about 8 mg or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks after the immediately preceding dose.
  • LLOQ lower limit of quantitation
  • the present invention provides a VEGF receptor fusion protein for use in a method
  • DR diabetic retinopathy
  • DME diabetic macular edema
  • the method comprises administering to an eye of the subject, one or more doses of about 8 mg or more of VEGF receptor fusion protein once every 12, 13, 14, 15, 16, 17, 18, 19 or 20 or 12-20 or 12-16 or 16-20 weeks.
  • the present invention provides aflibercept for use in the treatment or prevention of diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof, wherein the treatment or prevention comprises initiating the treatment with 1 injection of 8 mg aflibercept per month (every 4 weeks) for three consecutive doses followed by one or more injection once every 8 - 16 weeks or 8 - 20 weeks, wherein the concentration of aflibercept of each said dose is 114.3 mg/mL or wherein the application volume of each said dose is 70 pL.
  • the treatment interval between two subsequent administrations of 8 mg aflibercept is adjusted (increased/maintained/reduced) based on visual and/or anatomic outcomes such as but not limited to letter gain or letter loss in BCVA; increase or reduction in CRT; presence or absence of subretinal fluid; or presence or absence of hemorraghe or persistent or worsening DME.
  • the treatment interval is reduced by 2-4 weeks, 2 weeks, 3 weeks or by 4 weeks compared to the previous treatment interval in case said subject has been identified as one with meeting at least one of the following criteria for reduction of the treatment interval: > 5 letter or > 10 letter loss in BCVA; CRT of >300 or 320 pm; > 50 pm increase in CRT; or 2.
  • the treatment interval is extended by 2-4 weeks, 2 weeks, 3 weeks or by 4 weeks compared to the previous treatment interval in case said subject has been identified as one with meeting at least one of the following criteria for extending the treatment interval: ⁇ 5 letter ⁇ 10 letter loss in BCVA; CRT ⁇ 300 or 320 pm; > 50 pm decrease in CRT; absence of subretinal fluid; or absence of hemorraghe.
  • the present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic macular edema, in a subject in need thereof wherein the method comprises administering 8 mg VEGF receptor fusion protein (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by 8 mg VEGF receptor fusion protein (0.07 mL) via intravitreal injection once every 8 - 16 weeks (2 - 4 months, +/- 7 days) or every 8 - 20 weeks (2 - 5 months, +/- 7 days).
  • the present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic retinopathy (DR), in a subject in need thereof , wherein the method comprises administering 8 mg VEGF receptor fusion protein (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by 8 mg VEGF receptor fusion protein (0.07 mL) via intravitreal injection once every 8 - 16 weeks (2 - 4 months, +/- 7 days) or every 8 - 20 weeks (2 - 5 months, +/- 7 days).
  • DR diabetic retinopathy
  • the present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic macular edema (DME), in a subject in need thereof wherein the method comprises administering 8 mg VEGF receptor fusion protein (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by 8 mg VEGF receptor fusion protein (0.07 ml_) via intravitreal injection once every 12 weeks (2 - 4 months, +/- 7 days).
  • DME diabetic macular edema
  • the present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic retinopathy (DR), in a subject in need thereof wherein the method comprises administering 8 mg VEGF receptor fusion protein (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by 8 mg VEGF receptor fusion protein (0.07 mL) via intravitreal injection once every 12 weeks (2 - 4 months, +/- 7 days).
  • DR diabetic retinopathy
  • the present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic macular edema (DI E), in a subject in need thereof wherein the method comprises administering 8 mg VEGF receptor fusion protein (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by 8 mg VEGF receptor fusion protein (0.07 mL) via intravitreal injection once every 16 weeks (2 - 4 months, +/- 7 days).
  • DI E diabetic macular edema
  • the present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic retinopathy (DR), in a subject in need thereof wherein the method comprises administering 8 mg VEGF receptor fusion protein (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by 8 mg VEGF receptor fusion protein (0.07 mL) via intravitreal injection once every 16 weeks (2 - 4 months, +/- 7 days).
  • DR diabetic retinopathy
  • the present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic macular edema (DIME), in a subject in need thereof wherein the method comprises administering 8 mg VEGF receptor fusion protein (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by 8 mg VEGF receptor fusion protein (0.07 mL) via intravitreal injection once every 20 weeks (2 - 4 months, +/- 7 days).
  • DIME diabetic macular edema
  • the present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic retinopathy (DR), in a subject in need thereof wherein the method comprises administering 8 mg VEGF receptor fusion protein (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by 8 mg VEGF receptor fusion protein (0.07 mL) via intravitreal injection once every 20 weeks (2 - 4 months, +/- 7 days).
  • the present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof:
  • the method comprises, after 1 month, administering to the subject the initial 8 mg dose of VEGF receptor fusion protein and, 1 month thereafter, the 1st 8 mg secondary dose of VEGF receptor fusion protein; and, 1 month thereafter, the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the first 8 mg secondary dose of VEGF receptor fusion protein and, 1 month thereafter, the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the 2nd 8 mg secondary dose of VEGF receptor fusion protein and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the 1st 8 mg maintenance dose of VEGF receptor fusion protein and all further 8 mg maintenance doses of VEGF receptor fusion protein every 12 or 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after another 1 month, administering to the subject the initial 8 mg dose of VEGF receptor fusion protein and, 1 month thereafter, the 1st 8 mg secondary dose of VEGF receptor fusion protein; and 1 month thereafter, the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after another 1 month, administering to the subject a first 8 mg secondary dose of VEGF receptor fusion protein and, 1 month thereafter, the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after another 1 month, administering to the subject the 2nd 8 mg secondary dose of VEGF receptor fusion protein and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after another 1 month, administering to the subject the 1st 8 mg maintenance dose of VEGF receptor fusion protein and all further 8 mg maintenance doses of VEGF receptor fusion protein every 12 or 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after another 1 month, administering to the subject the initial 8 mg dose of VEGF receptor fusion protein and, 1 month thereafter, the 1st 8 mg secondary dose of VEGF receptor fusion protein; and 1 month thereafter, the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after another 1 month, administering to the subject the first 8 mg secondary dose of VEGF receptor fusion protein and, 1 month thereafter, the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen; (11) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st 2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd 2 mg secondary dose of VEGF receptor fusion protein after another 1 month, then the method comprises, after another 1 month, administering to the subject the 2nd 8 mg secondary dose of VEGF receptor fusion
  • the method comprises, after 2 months, administering to the subject the 1st 8 mg maintenance dose of VEGF receptor fusion protein and, all further 8 mg maintenance doses of VEGF receptor fusion protein every 12 or 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the initial 8 mg dose of VEGF receptor fusion protein and 1 month thereafter, the 1st 8 mg secondary dose of VEGF receptor fusion protein; and 1 month thereafter, the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the first 8 mg secondary dose of VEGF receptor fusion protein and 1 month thereafter, the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the 2nd 8 mg secondary dose of VEGF receptor fusion protein and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 2 months, administering to the subject the 1st 8 mg maintenance dose of VEGF receptor fusion protein and all further 8 mg maintenance doses of VEGF receptor fusion protein every 12 or 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 2 months, administering to the subject the initial 8 mg dose of VEGF receptor fusion protein and,
  • the method comprises, after 2 months, administering to the subject the first 8 mg secondary dose of VEGF receptor fusion protein and, 1 month thereafter, the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 2 months, administering to the subject the 2nd 8 mg secondary dose of VEGF receptor fusion protein and, 12 or 16 or 20 weeks thereafter, one or more 12 or 16 weekly 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 2 months, administering to the subject the 1st 8 mg maintenance dose of VEGF receptor fusion protein and, all further 8 mg maintenance doses of VEGF receptor fusion protein every 12 or 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, 2 months after the last VEGF receptor fusion protein maintenance dose, administering to the subject the initial 8 mg dose of VEGF receptor fusion protein and, 1 month thereafter, the 1st 8 mg secondary dose of VEGF receptor fusion protein; and 1 month thereafter, the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, 2 months after the last VEGF receptor fusion protein maintenance dose administering to the subject the first 8 mg secondary dose of VEGF receptor fusion protein and, 1 month thereafter, the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, 2 months after the last VEGF receptor fusion protein maintenance dose, administering to the subject the 2nd 8 mg secondary dose of VEGF receptor fusion protein and, 12 or 16 or 20 weeks thereafter, one or more 12 or 16 or 20 weekly 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen; or
  • the method comprises, 2 months after the last VEGF receptor fusion protein maintenance dose, administering to the subject the 1st 8 mg maintenance dose of VEGF receptor fusion protein and, all further 8 mg maintenance doses of VEGF receptor fusion protein every 12 or 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen; wherein,
  • said HDq12 dosing regimen comprises: a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks after the immediately preceding dose;
  • said HDq16 dosing regimen comprises: a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 16 weeks after the immediately preceding dose; and
  • said HDq20 dosing regimen comprises: a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 20 weeks after the immediately preceding dose.
  • the present invention provides aflibercept for use in the treatment or prevention of diabetic macular edema or diabetic retinopathy, in a subject in need thereof, comprising administering to an eye of the subject, a single initial dose 8 mg aflibercept, followed by one or more tertiary doses of about 8 mg of aflibercept; wherein each tertiary dose is administered about 8, 12, 16, or 20 weeks after the immediately preceding dose.
  • the subject is not a treatment naive subject, or the subject was pre-treated with a VEGF antagonist or preferably the subject was pre-treated with 8 mg aflibercept or with 2 mg aflibercept.
  • the present invention provides aflibercept for use in the treatment or prevention of diabetic macular edema or diabetic retinopathy, in a subject which was pre-treated with 2 mg aflibercept, comprising administering to an eye of the subject a single initial dose of about 8 mg aflibercept, followed by one or more secondary doses of about 8 mg of aflibercept, followed by one or more tertiary doses of about 8 mg aflibercept, wherein each secondary dose is administered about 4 weeks after the immediately preceding dose and wherein each tertiary dose is administered about 8, 10, 12, 14, 16, 18 or 20 weeks after the immediately preceding dose.
  • the administration of one or more doses of 8 mg aflibercept to an eye of the subject is according to HDq12, HDq16, HDq20, or treat and extent dosing regimen.
  • the present invention provides a VEGF receptor fusion protein for use in the treatment or prevetion of diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof who has been on a dosing regimen for treating or preventing said disorder wherein:
  • the method comprises, after 1 month, administering to the subject the first 8 mg secondary dose of VEGF receptor fusion protein and 1 month thereafter, administering the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, administering one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen; or
  • the method comprises, after another 1 month, administering to the subject the 2nd 8 mg secondary dose of VEGF receptor fusion protein; and then, every 12 or 16 or 20 weeks thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen; or
  • the method comprises, after 12 or 16 or 20 weeks administering to the subject the 1st 8 mg maintenance dose of VEGF receptor fusion protein and all further 8 mg maintenance doses of VEGF receptor fusion protein every 12 or 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen; or
  • the subject has received an initial 8 mg dose of VEGF receptor fusion protein & a 1st 8 mg secondary dose of VEGF receptor fusion protein after 1 month & the 2nd 8 mg secondary dose of VEGF receptor fusion protein after another month, then every 12 or 16 or 20 weeks thereafter, the subject has received one or more 8 mg maintenance doses of VEGF receptor fusion protein; and, then the method comprises, after 12 or 16 or 20 weeks from the last maintenance dose of VEGF receptor fusion protein, administering to the subject one or more 8 mg maintenance doses of VEGF receptor fusion protein and all further 8 mg maintenance doses of VEGF receptor fusion protein every 12 or 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen; wherein,
  • said HDq12 dosing regimen comprises: a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks after the immediately preceding dose;
  • said HDq16 dosing regimen comprises: a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 16 weeks after the immediately preceding dose; and
  • said HDq20 dosing regimen comprises: a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 20 weeks after the immediately preceding dose.
  • the present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of angiogenic eye disorder, in a subject in need thereof who has been on a dosing regimen for treating or preventing the disorder calling for a single initial dose of about 2 mg of VEGF receptor fusion protein, followed by one or more secondary doses of about 2 mg of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 2 mg of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose; and wherein the subject is at any phase of the 2 mg VEGF receptor fusion protein dosing regimen, comprising administering to an eye of the subject, an 8 mg dose of VEGF receptor fusion protein, evaluating the subject in about 8 or 10 or 12 weeks after said administering and, if, in the judgment of the treating physician dosing every 12 weeks or every 16 weeks is appropriate, then continuing
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy or diabetic macular edema, in a subject in need thereof, wherein the treatment or prevention comprises administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses, preferably 2 dosis, of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 or 16 weeks after the immediately preceding dose; further comprising, after receiving one or more of said tertiary doses about 12 or 16 after the immediately preceding dose, lengthening the tertiary dose interval from
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 or 16 or 20 weeks after the immediately preceding dose; further comprising, after receiving one or more of said tertiary doses about 12 or 16 or 20 weeks after the immediately preceding dose, shortening the tertiary dose interval from
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject 3 doses of about 8 mg VEGF receptor fusion protein in a formulation that comprises about 114.3 mg/ml VEGF receptor fusion protein at an interval of once every 4 weeks; wherein after said 3 doses, administering one or more doses of the VEGF receptor fusion protein at an interval which is lengthened up to 12, 16 or 20 weeks.
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by 2 secondary doses of about 8 mg or more of the VEGF receptor fusion protein, wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and, after said doses, a) determining if the subject meets at least one criterion for reducing or lengthening one or more intervals by 2 weeks, 3 weeks, 4 weeks or 2-4 weeks between doses of the VEGF receptor fusion protein; and b) if said determination is made, administering further doses of the VEGF receptor fusion protein at said reduced or lengthened intervals between doses wherein criteria for lengthening the interval include:
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema, in a subject in need thereof that has been pre-treated with one or more 2 mg doses of VEGF receptor fusion protein, comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks after the immediately preceding dose.
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, in a subject in need thereof, comprising administering to an eye of the subject,
  • a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder wherein the treatment or prevention comprises, prior to each administration, providing
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema in a subject in need thereof, wherein the subject has been receiving a dosing regimen for treating or preventing diabetic retinopathy and/or diabetic macular edema calling for: a single initial dose of about 2 mg of VEGF receptor fusion protein, followed by 4 secondary doses of about 2 mg of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 2 mg of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose;wherein the subject is at any phase (initial dose, secondary dose or tertiary dose) of the 2 mg VEGF receptor fusion protein dosing regimen.
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema in a subject in need thereof, wherein 8 mg of a VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising about 103-126 mg/ml VEGF receptor fusion protein, histidine-based buffer and arginine.
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema in a subject in need thereof wherein 8 mg of a VEGF receptor fusion protein is an aqueous pharmaceutical formulation comprising about 114.3 mg/ml VEGF receptor fusion protein, histidine-based buffer and arginine.
  • the present invention provides aflibercept for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema in a subject in need thereof wherein the >8 mg aflibercept is in an aqueous pharmaceutical formulation wherein the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema in a subject in need thereof wherein the >8 mg VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising: at least about 100 mg/ml of a VEGF receptor fusion protein; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema in a subject in need thereof wherein 8 mg of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising
  • VEGF receptor fusion protein • >100 mg/ml VEGF receptor fusion protein, histidine-based buffer and L-arginine; • 140 mg/ml aflibercept; 20 mM histidine-based buffer; 5 % sucrose; 0.03 % polysorbate 20; 10 mM L-arginine; pH 5.8;
  • aflibercept • about 114.3 mg/mL aflibercept; arginine monohydrochloride; histidine; histidine hydrochloride, monohydrate; polysorbate 20; sucrose and water for injection.
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema in a subject in need thereof wherein the subject achieves and/or maintains one or more of,
  • DRSS Diabetic Retinopathy Severity Scale
  • CTR central retinal thickness
  • SD-OCT spectral domain optical coherence tomography
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema in a subject in need thereof, wherein the subject achieves and/or maintains one or more of:
  • Non-inferior BVCA compared to that of aflibercept which is intravitreally dosed at 2 mg approximately every 4 weeks for the first 3, 4 or 5 injections followed by 2 mg approximately once every 8 weeks or once every 2 months;
  • BCVA (according to ETDRS letter score) of about 7, 8 or 9 letters by week 60 from start of treatment, wherein the baseline BCVA is about 61 , 62 or 63;
  • BCVA (according to ETDRS letter score) of at least about 69 letters by week 48 or 60 from start of treatment
  • BCVA score (according to ETDRS letter score) of about 69, 70, 71 , 72 or 73;
  • BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9 wherein the BCVA at any point between week 36 to 48 is about 60 or 70;
  • BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9, wherein the BCVA at any point between week 48 to 60 is about 69, 70, 71 , 72 or 73;
  • EDRS Early Treatment Diabetic Retinopathy Study
  • DRSS Diabetic Retinopathy Severity Scale
  • DRSS diabetic retinopathy severity scale
  • Retina without fluid total fluid, intraretinal fluid [IRF] and/or subretinal fluid [SRF]
  • OCT optical coherence tomography
  • Retina without fluid total fluid, intraretinal fluid [IRF] and/or subretinal fluid [SRF]) at the foveal center by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment;
  • OCT optical coherence tomography
  • a change in central retinal thickness by 48 weeks after initiation of treatment of about -171 or -172 or -171.7 micrometers when on the HDq12 regimen; or of about -148 or - 149 or -148.3 or -149.4 micrometers when on the HDq16 regimen; • A change in central retinal thickness, by 60 weeks after initiation of treatment of about -181 .95 or -176.24 micrometers when on the HDq12 regimen; or of about -166.26 or - 167.18 micrometers when on the HDq16 regimen;
  • CTR central retinal thickness
  • free aflibercept in plasma of about 0.0767 (+0.0436) mg/l wherein, at baseline, free aflibercept in plasma not detectable, wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks;
  • adjusted bound aflibercept in plasma of about 0.00731 (+0.0279) mg/l wherein, at baseline, there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks;
  • adjusted bound aflibercept in plasma of about 0.0678 (+0.0486) mg/l wherein, at baseline, there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks;
  • adjusted bound aflibercept in plasma of about 0.138 (+0.0618) mg/l wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks;
  • adjusted bound aflibercept in plasma of about 0.259 (+0.126) mg/l wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks;
  • adjusted bound aflibercept in plasma of about 0.346 (+0.151) mg/l wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks;
  • adjusted bound aflibercept in plasma of about 0.374 (+0.110) mg/l wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks;
  • adjusted bound aflibercept in plasma of about 0.343 (+0.128) mg/l wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks;
  • adjusted bound aflibercept in plasma of about 0.269 (+0.149) mg/l wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks;
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema in a subject in need thereof wherein
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema in a subject in need thereof wherein the interval between doses of 8 mg VEGF receptor fusion protein is adjusted (increased/maintained/reduced) based on visual and/or anatomic outcomes.
  • the present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and/or diabetic macular edema in a subject in need thereof wherein the doses of 8 mg VEGF receptor fusion protein are administered according to pro re nata (PRN), capped PRN or treat and extend (T&E) dosing regimen.
  • PRN pro re nata
  • T&E treat and extend
  • the present invention also provides a kit comprising i) a container comprising a VEGF receptor fusion protein, preferably aflibercept and ii) instruction for use of the VEGF fusion protein.
  • the container is a vial or a pre-filled syringe.
  • the vial a type I glass vial containing a nominal fill volume of abut 0.26 mL solution for intravitreal injection.
  • the container comprises the VEGF receptor fusion protein at a concentration of more or equal to 100 mg/mL or the container comprises aflibercept at a concentration of about 114.3 mg/mL.
  • the instruction for use comprising instruction for use of the VEGF fusion protein or aflibercept for the treatment of DME and /or AMD.
  • the instruction for use comprises the information that i) the container comprises 8 mg (114.3 mg/mL) aflibercept solution for intravitreal injection, ii) each single-dose vial provides a usable amount to deliver a single dose of 70 microliters containing 8 mg aflibercept to adult patients, iii) the recommended dose is 8 mg aflibercept (equivalent to 70 microliters solution for injection), iv) 8 mg aflibercept treatment is initiated with 1 injection per month (every 4 weeks) for 3 consecutive doses, v) injection intervals may then be extended up to every 16 weeks or 20 weeks vi) the treatment interval may be adjusted based on the physician’s judgement of visual and/or anatomic outcomes and /or vii) that 8 mg aflibercept / 0.07 mL is provided as a
  • Figure 1 Summary of PHOTON clinical trial.
  • Figure 2 Key eligibility criteria (inclusion criteria and exclusion criteria) of PHOTON clinical trial.
  • Figure 4 Criteria for dose regimen modifications of PHOTON clinical trial.
  • Figure 5 Patient disposition at week 48 in PHOTON clinical trial.
  • Figure 6 Baseline demographics of subjects in PHOTON clinical trial.
  • Figure 7 Baseline characteristics of the study eye of subjects in PHOTON clinical trial.
  • Figure 8 Mean number of injections through week 48 in PHOTON clinical trial.
  • Figure 9* Mean change in Best Corrected Visual Acuity (BCVA) through week 48 in PHOTON clinical trial. Least squares mean change from baseline at week 48 shown.
  • the present invention includes methods for achieving approximately the indicated improvement in BVCA by the indicated timepoint when receiving the indicated treatment regimen for treating
  • Figure 10 Percentage of subjects maintaining Q12 week and Q16 week intervals through week 48 in PHOTON clinical trial.
  • Figure 11 Key secondary endpoint of percentage of subjects with >2 step improvement in Diabetic Retinopathy Severity Scale (DRSS) at week 48 in PHOTON clinical trial.
  • DRSS Diabetic Retinopathy Severity Scale
  • Figure 12 Percentage of subjects without retinal fluid at foveal center at week 48 in PHOTON clinical trial.
  • Figure 13* Mean change from baseline in central retinal thickness through week 48 in PHOTON clinical trial. Various matched intervals are highlighted in three insets.
  • the present invention includes methods for achieving approximately the indicated reduction in central retinal thickness by the indicated timepoint when receiving the indicated treatment regimen for treating DR and/or DME.
  • Figures 14A, 14B and 14C Ocular serious Treatment Emergent Adverse Events
  • TEAEs through week 48 in PHOTON clinical trial (Fig. 14A); Most Frequent Adverse Events (AEs) through week 48 (Fig. 14B); Non-Ocular Safety through week 48 (Fig. 14C).
  • Figure 15 Treatment emergent intraocular inflammation through week 48 in PHOTON clinical trial.
  • Figure 16 Mean change from baseline in intraocular pressure through week 48 in PHOTON clinical trial.
  • Figure 17 Percentage of subjects meeting intraocular pressure criteria in PHOTON clinical trial.
  • Figure 18 Non-Ocular Serious TEAEs >1% through week 48 in PHOTON clinical trial.
  • FIG 19 Treatment emergent Anti-Platelet Trialists’ Collaboration (APTC) events through week 48 in PHOTON clinical trial.
  • Figure 20 Treatment emergent hypertension events though week 48 in PHOTON clinical trial.
  • Figure 21 Potentially Clinically Significant Values (PCSVs) for blood pressure through week 48 in PHOTON clinical trial.
  • Figure 22 Mean change from baseline in systolic blood pressure through week 48 in PHOTON clinical trial. Baseline to week 9 and mean baseline shown in insets.
  • Figure 23 Mean change from baseline in diastolic blood pressure through week 48 in PHOTON clinical trial. Baseline to week 9 and mean baseline shown in insets.
  • Figure 24 Deaths through week 48 in PHOTON clinical trial.
  • Figures 25A and 25B (A)Mean Change from Baseline in BCVA Score (ETDRS Letters) in Study Eye through Week 60, OC (Full Analysis Set): (B) Least Square Mean Change from Baseline in BCVA Score (ETDRS Letters) in Study Eve through Week 60 (Full Analysis Set).
  • BCVA best-corrected visual activity
  • ETDRS Early Treatment of Diabetic Retinopathy Study
  • HD high dose
  • OC observed cases
  • SE standard error.
  • OC Observations after an ICE defined for the primary estimand were excluded.
  • Figures 26A and 26B (A) Mean Change from Baseline in Central Retinal Thickness (microns) by Visit through Week 60, OC (Full Analysis Set) (B) Least Square Mean Change from Baseline in Central Retinal Thickness (microns) by Visit through Week 60, OC (Full Analysis Set).
  • 2q8 Aflibercept 2 mg administered every 8 weeks after 5 initial injections at 4-week intervals
  • HDq12 High dose aflibercept 8 mg administered every 12 weeks after 3 initial injections at 4-week intervals
  • HDq16 High dose aflibercept 8 mg administered every 16 weeks after 3 initial injections at 4-week intervals.
  • ICE intercurrent events;
  • Figure 27 Mean ( ⁇ SD) Concentrations (mg/l) of Free Aflibercept in Plasma by Nominal Time and Treatment in Participants with DME with Unilateral Treatment in the Dense PK Sampling sub-study (Study VGFTe-HD-DME-1934, Log-Scaled, fDPKSI).
  • HDq12+HDq16 combined data from treatment groups HDq12 and HDq16. Patients in the dense PK sub-study only received aflibercept injections unilaterally.
  • Figure 28 Mean ( ⁇ SD) Concentrations (mg/l) of Adjusted Bound Aflibercept in Plasma by Nominal Time and Treatment in Participants with DME with Unilateral Treatment in the Dense PK Sampling sub-study (Study VGFTe-HD-DME-1934, Log-Scaled, fDPKSI).
  • Figure 29 Mean ( ⁇ SD) Concentrations (mg/l) of Free Aflibercept in Plasma by Nominal Time and Treatment Group in Participants with DME in the Sparse PK Sampling Study (Study VGFTe-HD-DME-1934, Log-Scaled, IPKASl).
  • PKAS Pharmacokinetics analysis set. Note: T able under the figure presents the number of subjects contributing to the statistics for the corresponding visits/timepoints and treatment groups. Concentrations below the LLOQ were set to LLOQ/2. Post-dose samples and samples collected during the dense PK sub-study (from post dose on Day 0 through Day 21) were excluded.
  • SD Standard deviation
  • DME Diabetic macular edema
  • 2q8 2 mg intravitreal aflibercept every 8 weeks following 5 initial monthly doses
  • HDq12 High-dose (8 mg) intravitreal aflibercept every 12 weeks following 3 initial monthly doses
  • HDq16 High-dose (8 mg) intravitreal aflibercept every 16 weeks following 3 initial monthly doses
  • FIG. 31 Structural Representation of a Population Pharmacokinetic Model Following IV, SC, and IVT Administration of Aflibercept.
  • CMT compartment
  • IV intravenous
  • IVT intravitreal
  • K20 elimination rate constant for free aflibercept
  • K40 elimination rate constant for adjusted bound aflibercept
  • K62 rate of absorption from subcutaneous injection depot compartment
  • K70 elimination rate constant from tissue (platelet) compartment
  • QE inter-compartmental clearance between ocular compartment and central compartment of free aflibercept
  • QF1 and QF2 inter-compartmental clearances of free aflibercept
  • VMK24, KM saturable Michaelis-Menten type binding of free aflibercept with VEGF
  • VMK27, KMK27 saturable elimination from plasma compartment to tissue compartment (platelets)
  • CMT 2 and CMT 4 are both representative of the plasma compartment and volumes are assumed to be equal.
  • Figure 32 Mean ( ⁇ SD) Concentrations (mq/l) of Free and Adjusted Bound Aflibercept Over 28 Days for Single 2 mg and 8 mg IVT Doses of Aflibercept in nAMD or DME in the Dense PK Sub-studies (DPKS, Log-Scaled).
  • LQ below limit of quantification
  • DME Diabetic Macular Edema
  • DPKS dense pharmacokinetic sub-studies
  • HDq12 aflibercept 8 mg administered every 12 weeks following 3 initial monthly injections
  • HDq16 aflibercept 8 mg administered every 16 weeks following 3 initial monthly injections
  • IVT intravitreally
  • LLOQ lower limit of quantification
  • N number of participants
  • nAMD neovascular age-related macular degeneration
  • HD aflibercept data for the first 28 days is a combination of data from participants who received HDq12 or HDq16.
  • One participant in PULSAR with an outlier free aflibercept concentration at day 28 that is greater than 10-fold of the mean concentration is excluded. Records after fellow-eye treatment are excluded.
  • Data Source drug concentration data from the week 48 database lock for PULSAR and PHOTON and final lock for CANDELA.
  • Figure 33 Observed and Model-Predicted Concentrations (mq/l) of Free and Adjusted Bound Aflibercept in Plasma Over 28 days After a Single IVT Injection for Participants with nAMD or DME in the Dense PK Sub-studies (DPKS), Stratified by Dose and Population.
  • DME diabetic macular edema
  • IVT intravitreally
  • LLOQ lower limit of quantitation
  • nAMD neovascular age-related macular degeneration
  • PK pharmacokinetic Observed concentrations below the lower limit of quantitation (LLOQ; 0.0156 mg/L for free and 0.0224 mg/L for adjusted bound aflibercept) were set to LLOQ/2.
  • Data source Drug concentration data from dense PK sub-study in PHOTON, PULSAR, and CANDELA.
  • Figure 34 Overlay of Observed and Model-Predicted Concentrations (mg/l) of Free and Adjusted Bound Aflibercept in Plasma for Combined nAMD and DME Populations.
  • 2q8 aflibercept 2 mg administered every 8 weeks, after 3 initial injections at 4-week intervals
  • 2q12 aflibercept 2 mg administered every 12 weeks, after 3 initial injections at 4-week intervals
  • DME diabetic macular edema
  • HDq12 aflibercept 8 mg administered every 12 weeks following 3 initial monthly injections
  • HDq16 aflibercept 8 mg administered every 16 weeks following 3 initial monthly injections
  • IVT intravitreally
  • LLOQ lower limit of quantification
  • nAMD neovascular age-related macular degeneration Observed concentrations below the lower limit of quantitation (LLOQ; 0.0156 mg/L for free and 0.0224 mg/L for adjusted bound aflibercept) were set to LLOQ/2.
  • DME diabetic macular edema
  • HD aflibercept 8 mg
  • IVT intravitreal
  • nAMD neurovascular age- related macular degeneration
  • PI prediction interval
  • PK pharmacokinetics
  • QE intercompartmental clearance between ocular compartment and central compartment of free aflibercept Adjusted LLOQ (0.0624 pg), set as the LLOQ of free aflibercept in plasma (that is, 0.0156 mg/L) times the assumed volume of the study eye compartment in the PK model (that is, 4 mL).
  • Figure 36 Mean ( ⁇ SD) Concentrations (mg/l) of Free and Adjusted Bound Aflibercept Over 28 Days for Single 2 mg and 8 mg IVT Doses of Aflibercept in Participants with nAMD in the Dense PK Sub-studies (DPKS, Log-Scaled) - No Outlier.
  • DME diabetic macular edema
  • DPKS dense pharmacokinetic sub-studies
  • HDq12 aflibercept 8 mg administered every 12 weeks following 3 initial monthly injections
  • HDq16 aflibercept 8 mg administered every 16 weeks following 3 initial monthly injections
  • IVT intravitreally
  • LLOQ lower limit of quantification
  • N number of participants
  • nAMD neovascular age-related macular degeneration
  • PK pharmacokinetic
  • DME diabetic macular edema
  • DPKS dense pharmacokinetic sub-studies
  • HDq12 aflibercept 8 mg administered every 12 weeks following 3 initial monthly injections
  • HDq16 aflibercept 8 mg administered every 16 weeks following 3 initial monthly injections
  • IVT intravitreally
  • LLOQ lower limit of quantification
  • N number of participants
  • nAMD neovascular age-related macular degeneration
  • PK pharmacokinetic
  • Figure 38 Mean ( ⁇ SD) Concentrations (mq/l) of Free and Adjusted Bound Aflibercept Over 28 Days for Single 2 mg and 8 mg IVT Doses of Aflibercept in Participants with DME in the Dense PK Sub-studies (DPKS, Log-Scaled).
  • BLQ below limit of quantification
  • DME diabetic macular edema
  • DPKS dense pharmacokinetic analysis set
  • HDq12 aflibercept 8 mg administered every 12 weeks following 3 initial monthly injections
  • HDq16 aflibercept 8 mg administered every 16 weeks following 3 initial monthly injections
  • IVT intravitreally
  • LLOQ lower limit of quantification
  • N number of participants
  • nAMD neovascular age-related macular degeneration
  • 8 mg data for the first 28 days is a combination of data from participants who received HDq12 or HDq16.
  • the Concentration is subtracted by baseline concentration if participants took the Aflibercept prior to study drug started within 12 weeks and the baseline concentration is > BLQ.
  • Data source drug concentration data from the week 48 lock for PHOTON.
  • Drug concentration data from VGFT-OD-0706 historical data are included as a reference. Records after fellow-eye treatment are excluded.
  • Figure 39 Overlay of Observed and Model-Predicted Concentrations (mq/l) of Free and Adjusted Bound Aflibercept in Plasma for Participants with nAMD.
  • 2q8 aflibercept 2 mg administered every 8 weeks, after 3 initial injections at 4-week intervals
  • 2q12 aflibercept 2 mg administered every 12 weeks, after 3 initial injections at 4-week intervals
  • DME diabetic macular edema
  • HDq12 aflibercept 8 mg administered every 12 weeks following 3 initial monthly injections
  • HDq16 aflibercept 8 mg administered every 16 weeks following 3 initial monthly injections
  • IVT intravitreally
  • LLOQ lower limit of quantitation
  • nAMD neovascular age-related macular degeneration
  • PK pharmacokinetics Observed concentrations below the lower limit of quantitation (LLOQ; 0.0156 mg/L for free and 0.0224 mg/L for adjusted bound aflibercept) were set to LLOQ/2
  • Figure 40 Overlay of Observed and Model-Predicted Concentrations (mg/l) of Free and Adjusted Bound Aflibercept in Plasma for Participants with Diabetic Macular Edema in study PHOTON.
  • 2q8 aflibercept 2 mg administered every 8 weeks, after 3 initial injections at 4-week intervals
  • HDq12 aflibercept 8 mg administered every 12 weeks, after 3 initial injections at 4-week intervals
  • HDq16 aflibercept 8 mg administered every 16 weeks, after 3 initial injections at 4-week intervals
  • IVT intravitreally
  • LLOQ lower limit of quantitation Data from PHOTON.
  • the present invention provides, in part, a safe and effective high-dose aflibercept IVT injection which extends the maintenance dosing interval past 8 weeks, with at least similar functional and potentially improved anatomic outcomes.
  • the regimen exhibited an unexpectedly high level of durability in subjects which exceeded that which would have been expected simply based on administration of more aflibercept.
  • EYLEA has become the standard-of-care for diabetic macular edema (DME) and diabetic retinopathy (DR).
  • DME diabetic macular edema
  • DR diabetic retinopathy
  • Eylea is prescribed for DME and DR at a dose of 2 mg once a month for 5 doses followed by maintenance dosing every 8 weeks.
  • the dosing regimen of the present invention has demonstrated that a remarkably high percentage of subjects can be maintained on 12- and 16-week dosing intervals. In trials testing these dosing regimens, nearly 90% of subjects with diabetic macular edema were able to maintain a 16-week dosing regimen.
  • the magnitude of reduction in ocular clearance for the HD aflibercept drug product compared to the 2 mg Eylea drug product was greater than expected and attributed to an “HD aflibercept drug product effect”, a highly statistically significant effect in the population PK model that cannot be explained by just an increase in the dose from 2 mg to 8 mg.
  • the Population PK predicted median time for free aflibercept concentrations in plasma to reach the lower limit of quantification (LLOQ) following 2 mg IVT aflibercept was estimated to be 1.5 weeks compared to 3.50 weeks for 8 mg HD aflibercept.
  • the longer duration of systemic exposure to free aflibercept, representative of the movement of free aflibercept from the eye, for the HD aflibercept regimen was attributed to not only a higher administered dose and nonlinear systemic target-mediated elimination, but also to a 34% slower ocular clearance of free aflibercept.
  • the slower ocular clearance of the HD aflibercept drug product was predicted to provide a 6-week longer duration of efficacy compared to that of the 2 mg aflibercept drug product, as the population PK estimated time to achieve the free aflibercept amount in the ocular compartment for the 2q8 regimen at the end of an 8-week dosing interval occurs 6 weeks later for the HD aflibercept drug product.
  • Exposure-response analyses estimated that the slower ocular clearance for 8 mg aflibercept, attributable to the HD drug product effect, resulted in a 20.6% lower rate of dosing regimen modification (DRM) than would have been expected if the HD drug product had the same ocular clearance as 2 mg aflibercept.
  • DRM dosing regimen modification
  • Fluorescent reagents suitable for modifying nucleic acids including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probes (2003) Catalogue, Molecular Probes, Inc., Eugene, Oreg.; Sigma-Aldrich (2003) Catalogue, St. Louis, Mo.).
  • VEGF antagonists and VEGF receptor fusion proteins are at least partially free of other biological molecules from the cells or cell culture from which they are produced.
  • biological molecules include nucleic acids, proteins, other VEGF antagonists and VEGF receptor fusion proteins, lipids, carbohydrates, or other material such as cellular debris and growth medium.
  • An isolated VEGF antagonist or VEGF receptor fusion protein may further be at least partially free of expression system components such as biological molecules from a host cell or of the growth medium thereof.
  • isolated is not intended to refer to a complete absence of such biological molecules (e.g., minor or insignificant amounts of impurity may remain) or to an absence of water, buffers, or salts or to components of a pharmaceutical formulation that includes the VEGF antagonists or VEGF receptor fusion proteins.
  • a subject or patient is a mammal, for example a human, mouse, rabbit, monkey or non-human primate, preferably a human.
  • a subject or patient may be said to be “suffering from” an angiogenic eye disorder such as nAMD.
  • nAMD angiogenic eye disorder
  • Such a subject or patient has the disorder in one or both eyes.
  • a subject or patient preferably a human
  • has one or more of the following characteristics (presently or in the past):
  • BCVA Has Best Corrected Visual Acuity
  • EDRS Early Treatment Diabetic Retinopathy Study
  • Total lesion area of about 6 or 7 mm 2 , e.g., wherein the lesion type is occult, predominantly classic or minimally classic;
  • Type 1 or type 2 diabetes mellitus insulin dependent or non-insulin dependent (e.g., for about 15 or more years);
  • Hemoglobin A1C (%) of about 7 or 8 or more;
  • Body mass index of about 30 or 31 or more; and/or
  • a history of diabetic retinal oedema, diabetic retinopathy, dry eye, vitreous detachment, retihopathy hypersensitive, retinal hemorrhage, cataract operation, retinal laser coagulation, and intraocular lens implant, hypertension, and/or, has or lacks any one or more of the following characteristics:
  • Vitreomacular traction or epiretinal membrane in an eye e.g., as evident on biomicroscopy or OCT that is thought to affect central vision;
  • HbA1c hemoglobin A1c
  • Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg);
  • the present invention includes a method for treating or preventing DR and/or DME, in a subject in need thereof
  • BCVA Early Treatment Diabetic Retinopathy Study
  • EDRS Early Treatment Diabetic Retinopathy Study
  • Type 1 or type 2 diabetes mellitus has Type 1 or type 2 diabetes mellitus; and/or,
  • HbA1c hemoglobin A1c
  • VEGF receptor fusion protein preferably aflibercept
  • secondary dose of about 8 mg or more of the VEGF receptor fusion protein
  • tertiary dose of about 8 mg or more of the VEGF receptor fusion protein
  • VEGF antagonists include molecules which interfere with the interaction between VEGF and a natural VEGF receptor, e.g., molecules which bind to VEGF or a VEGF receptor and prevent or otherwise hinder the interaction between VEGF and a VEGF receptor.
  • exemplary VEGF antagonists include anti-VEGF antibodies, anti- VEGF receptor antibodies, and VEGF receptor fusion proteins.
  • VEGF receptor fusion proteins such as aflibercept
  • aflibercept VEGF receptor fusion proteins
  • any of the VEGF antagonists described herein e.g., scFvs, DARPins, anti-VEGF antibodies
  • VEGF receptor fusion protein refers to a molecule that comprises one or more VEGF receptors or domains thereof, fused to another polypeptide, which interferes with the interaction between VEGF and a natural VEGF receptor, e.g., wherein two of such fusion polypeptides are associated thereby forming a homodimer or other multimer.
  • VEGF receptor fusion proteins may be referred to as a "VEGF-Trap" or “VEGF Trap”.
  • VEGF receptor fusion proteins within the context of the present disclosure that fall within this definition include chimeric polypeptides which comprise two or more immunoglobulin (Ig)-like domains of a VEGF receptor such as VEGFR1 (also known as Flt1) and/or VEGFR2 (also known as Flk1 or KDR), and may also contain a multimerizing domain (for example, an Fc domain).
  • VEGFR1 also known as Flt1
  • VEGFR2 also known as Flk1 or KDR
  • Fc domain multimerizing domain
  • VEGF1R2- FcAC1(a) is a molecule referred to as VEGF1R2- FcAC1(a) which is encoded by the nucleic acid sequence of SEQ ID NO:1 or nucleotides 79- 1374 or 79-1371 thereof.
  • VEGF1 R2-FcAC1(a) comprises three components:
  • VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2;
  • VEGFR2 component comprising amino acids 130 to 231 of SEQ ID NO:2;
  • a multimerization component (“FcAC1 (a)") comprising amino acids 232 to 457 of SEQ ID NO:2 (the C-terminal amino acids of SEQ ID NO:2, i.e., K458, may or may not be included in the VEGF receptor fusion proteins, see U.S. Patent No. 7,396,664 or 7,354,579, incorporated herein for all purposes). Note that amino acids 1 to 26 of SEQ ID NO:2 are the signal sequence.
  • the multimerizing component (MC) of a VEGF receptor fusion protein is derived from an IgG (e.g., IgG 1 ) Fc domain, then the MC has no fewer amino acids than are in amino acids 232 to 457 of SEQ ID NO:2. Thus, the IgG of the MC cannot be truncated to be shorter than 226 amino acids.
  • the VEGF receptor fusion protein comprises amino acids 27-458 or 27-457 of SEQ ID NO: 2 (e.g., in the form of a homodimer).
  • the VEGF receptor fusion protein comprises
  • an immunoglobin-like (Ig) domain 2 of a first VEGF receptor e.g., VEGFR1
  • a first VEGF receptor e.g., VEGFR1
  • VEGF receptor e.g., VEGFR2
  • a multimerizing component e.g., Fc domain of IgG including the hinge, CH2 and CH3 domains.
  • the VEGF receptor fusion protein has the following arrangement of said domains:
  • the present disclosure also includes, within its scope, high concentration formulations including, instead of a VEGF receptor fusion protein, a VEGF binding molecule or anti-VEGF antibody or antigen-binding fragments thereof or biopolymer conjugate thereof (e.g., KSI-301), e.g.,
  • bevacizumab e.g., at a concentration of about 80-90 or 88 mg/ml
  • ranibizumab e.g., at a concentration of about 20-40 mg/ml, e.g., 21-35, 21 or 35 mg/ml
  • an anti-VEGF aptamer such as pegaptanib (e.g., pegaptanib sodium), • a single chain (e.g., VL-VH) anti-VEGF antibody such as brolucizumab (e.g., at a concentration of about 200-400 or 200, 210, 400 or 420 mg/ml),
  • an anti-VEGF DARPin such as the Abicipar Pegol DARPin (e.g., at a concentration of about 70-140, 70 or 140 mg/ml), or
  • a bispecific anti-VEGF antibody e.g., which also binds to ANG2, such as RG7716 (faricimab) (e.g., at a concentration of about 100-400, 100, 105, 400 or 420 mg/ml).
  • the scope of the present invention includes embodiments wherein any of the formulations discussed herein include, in place of a VEGF receptor fusion protein, an anti-VEGF antibody or antibody fragment or other VEGF binding molecule as discussed herein (e.g., substituted with an anti-VEGF DARPin) at any of the concentrations discussed herein.
  • the present invention includes a formulation having 35 or 80 mg/ml ranibizumab, a buffer, a thermal stabilizer, a viscosity reducing agent and a surfactant.
  • DARPins are Designed Ankyrin Repeat Proteins. DARPins generally contain three to four tightly packed repeats of approximately 33 amino acid residues, with each repeat containing a p-turn and two anti-parallel a-helices. This rigid framework provides protein stability whilst enabling the presentation of variable regions, normally comprising six amino acid residues per repeat, for target recognition.
  • an “anti-VEGF” antibody or antigen-binding fragment of an antibody refers to an antibody or fragment that specifically binds to VEGF.
  • Illustrative VEGF receptor fusion proteins include aflibercept (EYLEA®, Regeneron Pharmaceuticals, Inc.) or conbercept (sold commercially by Chengdu Kanghong Biotechnology Co., Ltd.). See International patent application publication no. W02005/121176 or
  • Aflibercept and “conbercept” include biosimilar versions thereof.
  • a biosimilar version of a reference product e.g., aflibercept
  • aflibercept generally refers to a product comprising the identical amino acid sequence, but includes products which are biosimilar under the U.S. Biologies Price Competition and Innovation Act.
  • the present invention also includes embodiments including administering one or more further therapeutic agents in addition to VEGF antagonist, for example, administering (one or more doses of) a second VEGF antagonist, an antibiotic, anesthetic (e.g., local anesthetic) to the eye receiving an injection, a non-steroidal anti-inflammatory drug (NSAID), a steroid (e.g., a corticosteroid, dexamethasone), triamcinolone acetonide (TA), methotrexate, rapamycin, an anti-tumor necrosis factor alpha drug (e.g., infliximab), daclizumab, and/or a complement component (e.g., C3 or C5) inhibitor.
  • NSAID non-steroidal anti-inflammatory drug
  • a steroid e.g., a corticosteroid, dexamethasone
  • TA triamcinolone acetonide
  • methotrexate rapamycin
  • the present invention includes methods in which the VEGF antagonist that is administered to the subject’s eye is contained within a pharmaceutical formulation.
  • the pharmaceutical formulation includes a VEGF antagonist along with a pharmaceutically acceptable carrier.
  • Other agents may be incorporated into the pharmaceutical formulation to provide improved transfer, delivery, tolerance, and the like.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the VEGF antagonist is administered.
  • Pharmaceutical formulations for use in a method of the present invention can be “high concentration”.
  • High concentration pharmaceutical formulations of the present invention include VEGF antagonist, e.g., VEGF receptor fusion protein, at a concentration of at least 41 mg/ml, of at least 80 mg/ml, of at least 100 mg/ml, of at least 125 mg/ml, of at least 140 mg/ml, of at least 150 mg/ml, of at least 175 mg/ml, of at least 200 mg/ml, of at least 225 mg/ml, of at least 250 mg/ml, or of at least 275 mg/ml.
  • VEGF antagonist e.g., VEGF receptor fusion protein
  • High concentration can refer to formulations that include a concentration of VEGF antagonist of from about 140 mg/ml to about 160 mg/ml, at least about 140 mg/ml but less than 160 mg/ml, from about 41 mg/ml to about 275 mg/ml, from about 70 mg/ml to about 75 mg/ml or from about 80 mg/ml to about 250 mg/ml.
  • the VEGF antagonist concentration in the formulation is about any of the following concentrations: 41 mg/ml; 42 mg/ml; 43 mg/ml; 44 mg/ml; 45 mg/ml; 46 mg/ml; 47 mg/ml; 48 mg/ml; 49 mg/ml; 50mg/ml; 51 mg/ml; 52 mg/ml; 53 mg/ml; 54 mg/ml; 55 mg/ml; 56 mg/ml; 57 mg/ml;
  • VEGF antagonist concentrations are contemplated herein, as long as the concentration functions in accordance with embodiments herein.
  • a pharmaceutical formulation for use in a method of the present invention is of such a concentration as to contain about 4, 6, 8, 10, 12, 14, 16, 18 or 20 mg VEGF receptor fusion protein (e.g., aflibercept), or the amount of such protein in any of the acceptable doses thereof which are discussed herein, in about 100 pl or less, about 75 pl or less or about 70 pl or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl;
  • VEGF receptor fusion protein e.g., aflibercept
  • the present invention includes methods of using (as discussed herein) any of the formulations set forth under “Illustrative Formulations” herein, but wherein the concentration of the VEGF receptor fusion protein (e.g., aflibercept) is substituted with a concentration which is set forth in this section (“VEGF Receptor Fusion Proteins and Other VEGF inhibitors”).
  • concentration of the VEGF receptor fusion protein e.g., aflibercept
  • Buffers for use in pharmaceutical formulations herein that may be used in a method of the present invention refer to solutions that resist pH change by use of acid-base conjugates. Buffers are capable of maintaining pH in the range of from about 5.0 to about 6.8, and more typically, from about 5.8 to about 6.5, and most typically, from about 6.0 to about 6.5. In some cases, the pH of the formulation of the present invention is about 5.0, about 5.1 , about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1 , about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, or about 6.8.
  • Example buffers for inclusion in formulations herein include histidine-based buffers, for example, histidine and histidine hydrochloride or histidine acetate.
  • Buffers for inclusion in formulations herein can alternatively be phosphate-based buffers, for example, sodium phosphate, acetate-based buffers, for example, sodium acetate or acetic acid, or can be citrate-based, for example, sodium citrate or citric acid. It is also recognized that buffers can be a mix of the above, as long as the buffer functions to buffer the formulations in the above described pH ranges. In some cases, the buffer is from about 5 mM to about 25 mM, or more typically, about 5 mM to about 15 mM.
  • Buffers can be about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, or about 25 mM.
  • a histidine-based buffer is prepared using histidine and histidine monohydrochloride.
  • Surfactant for use herein refers to ingredients that protect the higher concentration of VEGF antagonist, e.g., VEGF receptor fusion protein, from various surface and interfacial induced stresses.
  • VEGF antagonist e.g., VEGF receptor fusion protein
  • surfactants can be used to limit or minimize VEGF receptor fusion protein aggregation, and promote protein solubility.
  • Suitable surfactants herein have been shown to be non-ionic, and can include surfactants that have a polyoxyethylene moiety.
  • Illustrative surfactants in this category include: polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350, and mixtures thereof.
  • Surfactants in the formulations can be present at from about 0.02% to about 0.1% weight per volume (w/v), and more typically, about 0.02% to about 0.04% (w/v). In some cases, the surfactant is about 0.02% (w/v), about 0.03% (w/v), about 0.04% (w/v), about 0.05% (w/v), about 0.06% (w/v), about 0.07% (w/v), about 0.08% (w/v), about 0.09% (w/v), or about 0.1% (w/v).
  • Thermal stabilizers for use in pharmaceutical formulations refers to ingredients that provide thermal stability against thermal denaturation of the VEGF antagonist, e.g., VEGF receptor fusion protein, as well as protect against loss of VEGF receptor fusion protein potency or activity.
  • Suitable thermal stabilizers include sugars, and can be sucrose, trehalose, sorbitol or mannitol, or can be amino acids, for example L-proline, L-arginine (e.g., L-arginine monohydrochloride), or taurine. Additionally, thermal stabilizers may also include substituted acrylamides or propane sulfonic acid, or may be compounds like glycerol.
  • the pharmaceutical formulations for use in a method herein include both a sugar and taurine, a sugar and an amino acid, a sugar and propane sulfonic acid, a sugar and taurine, glycerol and taurine, glycerol and propane sulfonic acid, an amino acid and taurine, or an amino acid and propane sulfonic acid.
  • formulations can include a sugar, taurine and propane sulfonic acid, glycerol, taurine and propane sulfonic acid, as well as L-proline, taurine and propane sulfonic acid.
  • Embodiments herein may have thermal stabilizers present alone, each independently present at a concentration of, or present in combination at a total concentration of, from about 2% (w/v) to about 10% (w/v) or 4% (w/v) to about 10% (w/v), or about 4% (w/v) to about 9% (w/v), or about 5% (w/v) to about 8% (w/v).
  • Thermal stabilizers in the formulation can be at a concentration of about 2% (w/v), about 2.5% (w/v), about 3% (w/v), about 4% (w/v), about 5% (w/v), about 6% (w/v), about 7% (w/v), about 8% (w/v), about 9% (w/v), about 10% (w/v) or about 20% (w/v).
  • these thermal stabilizers can be present in the formulations at about from 25 mM to about 100 mM, and more typically from about 50 mM to about 75 mM (as compared to the other thermal stabilizers).
  • Viscosity reducing agents typically are used to reduce or prevent protein aggregation.
  • Viscosity reducing agents for inclusion herein include: sodium chloride, magnesium chloride, D- or L-arginine (e.g., L-arginine monohydrochloride), lysine, or mixtures thereof.
  • viscosity reducing agents can be present at from about 10 mM to about 100 mM, and more typically from about 30 mM to about 75 mM, and even more typically from about 40 mM to about 70 mM.
  • the viscosity reducing agent is present at about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM or about 100 mM.
  • compositions for use in a method as set forth herein can also have a pharmaceutically acceptable viscosity for ocular administration, for example, intravitreal injection.
  • Viscosity generally refers to the measure of resistance of a fluid which is being deformed by either shear stress or tensile stress (typically measured by techniques known in the art, viscometer or rheometer, for example).
  • Typical viscosities of formulations for use in a method set forth herein are from about 5.0 cP (centipoise) to about 15 cP, from about 11 cP to about 14 cP, from about 12 cP to about 15 cP or from about 11 cP to about 12 cP.
  • formulation viscosity herein can be about 5.0 cP, about 6.0, about 7.1 cP, about 7.2 cP, about 7.3 cP, about 7.4 cP, about 7.5 cP, about 7.6 cP, about 10 cP, about 10.5 cP, about 11.0 cP, about 11.5 cP, about 12.0 cP, about 12.5 cP, about 13.0 cP, about 13.5 cP, about 14.0 cP, about 14.5 cP, or about 15.0 cP (e.g., when measured at 20°C).
  • embodiments herein do not require inclusion of an inorganic salt, or other viscosity reducing agent, to maintain these highly useful viscosities.
  • high concentration protein solutions require viscosity reducing agents to avoid protein aggregation and higher viscosity, making the formulations difficult for intravitreal injection and reducing the potency of the VEGF receptor fusion protein.
  • embodiments herein include methods of using formulations that have had substantially no, or no added, sodium chloride (NaCI), magnesium chloride (MgCh), D- or L-arginine (e.g., L-arginine hydrochloride), lysine or other viscosity reducing agent.
  • the osmolality of a formulation for use in a method of the present invention is less than or equal to about 506 mmol/Kg or from about 250 to about 506 mmol/Kg., e.g., about 250, 260, 270, 280, 290, 299, 300, 310, 314, 315, 316, 324, 343, 346, 349, 369, 384, 403, 426, 430 or 506 mmol/Kg. In an embodiment of the invention, the osmolality is lower than about 250 mmol/Kg.
  • Illustrative pharmaceutical formulations for use in the methods of the present invention include the following:
  • Formulation A 80 mg/ml aflibercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation B 80 mg/ml aflibercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation C 80 mg/ml aflibercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation D 80 mg/ml aflibercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.
  • Formulation E 80 mg/ml aflibercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation F 80 mg/ml aflibercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation G 80 mg/ml aflibercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation H 80 mg/ml aflibercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation I 80 mg/ml aflibercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.0 3% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation J 80 mg/ml aflibercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation K 80 mg/ml aflibercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation L 80 mg/ml aflibercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation M 150 mg/ml aflibercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation N 150 mg/ml aflibercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation O 150 mg/ml aflibercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation P 150 mg/ml aflibercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.
  • Formulation Q 150 mg/ml aflibercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation R 150 mg/ml aflibercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation S 150 mg/ml aflibercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation T 150 mg/ml aflibercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2 (e.g., 6.2), and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation II 150 mg/ml aflibercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation V 150 mg/ml aflibercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation W 150 mg/ml aflibercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation X 150 mg/ml aflibercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation Y 80 mg/ml conbercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation Z 80 mg/ml conbercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation AA 80 mg/ml conbercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation BB 80 mg/ml conbercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.
  • Formulation CC 80 mg/ml conbercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation DD 80 mg/ml conbercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation EE 80 mg/ml conbercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation FF 80 mg/ml conbercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation GG 80 mg/ml conbercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation HH 80 mg/ml conbercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation II 80 mg/ml conbercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation JJ 80 mg/ml conbercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation KK 150 mg/ml conbercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation LL 150 mg/ml conbercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation MM 150 mg/ml conbercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation NN 150 mg/ml conbercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.
  • Formulation 00 150 mg/ml conbercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation PP 150 mg/ml conbercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
  • Formulation QQ 150 mg/ml conbercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation RR 150 mg/ml conbercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation SS 150 mg/ml conbercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation TT 150 mg/ml conbercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation UU 150 mg/ml conbercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation VV 150 mg/ml conbercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
  • Formulation WW 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM histidine- based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 50 mM taurine, with a pH of 5.8.
  • VEGF receptor fusion protein e.g., aflibercept
  • 10 mM histidine- based buffer 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 50 mM taurine, with a pH of 5.8.
  • Formulation XX 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine- based buffer, 4 % (w/v) proline, 0.03 % (w/v) polysorbate 20, and 50 mM arginine (e.g., arginine hydrochloride), with a pH of 5.8.
  • VEGF receptor fusion protein e.g., aflibercept
  • 20 mM histidine- based buffer 4 % (w/v) proline, 0.03 % (w/v) polysorbate 20
  • 50 mM arginine e.g., arginine hydrochloride
  • Formulation YY 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine- based buffer, 2.5 % (w/v) sucrose, 2.0 % (w/v) proline, 0.03 % (w/v) polysorbate 20, and 50 mM taurine, with a pH of 5.8.
  • VEGF receptor fusion protein e.g., aflibercept
  • Formulation ZZ 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM histidine- based buffer, 2.5 % (w/v) sucrose, 2.0 % (w/v) proline, 0.03 % (w/v) polysorbate 20, and 50 mM arginine (e.g., arginine hydrochloride), with a pH of 5.8.
  • Formulation AAA 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine- based buffer, 5 % (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 50 mM PSA, with a pH of 5.8.
  • Formulation BBB 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine- based buffer, 2.5 % (w/v) sucrose, 2.0 % (w/v) proline, 0.03 % (w/v) polysorbate 20, and 50 mM PSA, with a pH of 5.8.
  • VEGF receptor fusion protein e.g., aflibercept
  • Formulation CCC 80, 100, 120 or 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 50 mM arginine (e.g., arginine hydrochloride), with a pH of 5.8.
  • VEGF receptor fusion protein e.g., aflibercept
  • 20 mM histidine-based buffer 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20
  • 50 mM arginine e.g., arginine hydrochloride
  • Formulation DDD 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM histidine- based buffer, 4 % (w/v) proline, 0.03 % (w/v) polysorbate 20, and 50 mM PSA, with a pH of 5.8.
  • Formulation EEE 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine- based buffer, 5 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20 and, optionally, no thermal stabilizer, with a pH of 5.8.
  • Formulation FFF 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10mM sodium phosphate, 5 % (w/v) sucrose and 0.03 % polysorbate 20 with a pH of 6.2.
  • VEGF receptor fusion protein e.g., aflibercept
  • 10mM sodium phosphate 10mM sodium phosphate
  • 5 % (w/v) sucrose 5 % (w/v) sucrose
  • 0.03 % polysorbate 20 with a pH of 6.2.
  • Formulation GGG 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03 % polysorbate 20; 50 mM sodium sulfate
  • VEGF receptor fusion protein e.g., aflibercept
  • Formulation HHH 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03 % polysorbate 20; 50 mM sodium thiocyanate
  • VEGF receptor fusion protein e.g., aflibercept
  • Formulation III 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose, 0.03 % polysorbate 20; 40 mM sodium citrate
  • Formulation JJJ 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% Sucrose, 0.03 % polysorbate 20; 50 mM glycine
  • Formulation KKK 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose, 0.03 % polysorbate 20; 50 mM sodium chloride
  • Formulation LLL 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 50 mM lysine
  • Formulation MMM 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium aspartate
  • VEGF receptor fusion protein e.g., aflibercept
  • Formulation NNN 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 50 mM sodium glutamate
  • Formulation OOO 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium citrate; 50 mM arginine (e.g., arginine hydrochloride)
  • Formulation PPP 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM glycine; 50 mM arginine (e.g., arginine hydrochloride)
  • Formulation QQQ 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium aspartate; 50 mM arginine (e.g., arginine hydrochloride)
  • VEGF receptor fusion protein e.g., aflibercept
  • 50 mM sodium aspartate 50 mM arginine (e.g., arginine hydrochloride)
  • Formulation RRR 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium glutamate; 50 mM arginine (e.g., arginine hydrochloride)
  • VEGF receptor fusion protein e.g., aflibercept
  • 50 mM sodium glutamate 50 mM arginine (e.g., arginine hydrochloride)
  • Formulation SSS 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM His, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 10 mM L-arginine (e.g., L-arginine hydrochloride)
  • Formulation TTT 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM His, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 100 mM L-arginine (e.g., L-arginine hydrochloride)
  • Formulation UUU 30 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2
  • Formulation VW 30 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2
  • VEGF receptor fusion protein e.g., aflibercept
  • Formulation WWW 60 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2
  • VEGF receptor fusion protein e.g., aflibercept
  • 10 % sucrose 10 mM phosphate
  • 0.03 % polysorbate 20 pH 6.2
  • Formulation XXX 60 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2
  • VEGF receptor fusion protein e.g., aflibercept
  • Formulation YYY 120 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2
  • VEGF receptor fusion protein e.g., aflibercept
  • 10 % sucrose 10 mM phosphate
  • 0.03 % polysorbate 20 pH 6.2
  • Formulation ZZZ 120 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2
  • VEGF receptor fusion protein e.g., aflibercept
  • Formulation AAAA 120 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, 50 mM NaCI, pH 6.2
  • Formulation BBBB 120 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, 50 mM NaCI, pH 6.2
  • VEGF receptor fusion protein e.g., aflibercept
  • Formulation CCCC 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM sodium phosphate, 5 % sucrose, 40 mM sodium chloride, 0.03 % PS20, pH 6.2
  • VEGF receptor fusion protein e.g., aflibercept
  • 10 mM sodium phosphate 10 mM sodium phosphate
  • 5 % sucrose 5 % sucrose
  • 40 mM sodium chloride 0.03 % PS20, pH 6.2
  • Formulation DDDD 80 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine- based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 50 mM L-arginine (e.g., L- arginine hydrochloride), with a pH of 5.8.
  • VEGF receptor fusion protein e.g., aflibercept
  • 20 mM histidine- based buffer 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20
  • 50 mM L-arginine e.g., L- arginine hydrochloride
  • Formulation EEEE 120.0 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., + 12 mg/ml), 20 mM histidine-based buffer (e.g., + 2 mM), 5 % (w/v) sucrose (e.g., + 0.5%), 0.03 % (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine hydrochloride) (e.g., + 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).
  • aflibercept e.g., + 12 mg/ml
  • 20 mM histidine-based buffer e.g., + 2 mM
  • 5 % (w/v) sucrose e.g., + 0.5%)
  • 0.03 % (w/v) polysorbate 20 e
  • Formulation FFFF 113.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., 102-125 mg/ml), 20 mM histidine-based buffer (e.g., + 2 mM), 5 % (w/v) sucrose (e.g., + 0.5%), 0.03 % (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., + 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).
  • aflibercept e.g., 102-125 mg/ml
  • 20 mM histidine-based buffer e.g., + 2 mM
  • 5 % (w/v) sucrose e.g., + 0.5%)
  • Formulation GGGG 114.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., 103-126 mg/ml), 10 mM histidine-based buffer, for example, including Histidine and Histine-HCI (e.g., + 1 mM), 5 % (w/v) sucrose (e.g., + 0.5%), 0.03 % (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., + 5 mM), with a pH of 5.8 (e.g., 5.6- 6.0 or 5.5-6.1).
  • aflibercept e.g., 103-126 mg/ml
  • 10 mM histidine-based buffer for example, including Histidine and Histine-HCI (e.g., + 1 mM), 5 % (w
  • Formulation HHHH 100.0 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., + 10 mg/ml), 20 mM histidine-based buffer (e.g., + 2 mM), 5 % (w/v) sucrose (e.g., + 0.5%), 0.03 % (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., + 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).
  • aflibercept e.g., + 10 mg/ml
  • 20 mM histidine-based buffer e.g., + 2 mM
  • 5 % (w/v) sucrose e.g., + 0.5%)
  • 0.03 % (w/v) polysorbate 20
  • Formulation Illi 133.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., + 13 mg/ml), 20 mM histidine-based buffer (e.g., + 2 mM), 5 % (w/v) sucrose (e.g., + 0.5%), 0.03 % (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., + 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).
  • aflibercept e.g., + 13 mg/ml
  • 20 mM histidine-based buffer e.g., + 2 mM
  • 5 % (w/v) sucrose e.g., + 0.5%)
  • 0.03 % (w/v) polysorbate 20
  • Formulation JJJJ 150 mg/ml aflibercept (e.g., aflibercept) (e.g., + 15 mg/ml), 10 mM sodium phosphate, 8% (w/v) sucrose (e.g., + 0.8%), 0.03% (w/v) polysorbate 20 (e.g., 0.02-0.04%) and 50 mM L-arginine (e.g., arginine hydrochloride), pH 6.2 (e.g., 6.0-6.4 or 5.9-6.5).
  • aflibercept e.g., aflibercept
  • sucrose e.g., + 0.8
  • polysorbate 20 e.g., 0.02-0.04%
  • 50 mM L-arginine e.g., arginine hydrochloride
  • pH 6.2 e.g., 6.0-6.4 or 5.9-6.5.
  • Formulation KKKK 114.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., + 14 mg/ml), 20 mM histidine-based buffer (e.g., + 2 mM), 5% (w/v) sucrose (e.g., + 0.5%), 0.03% (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., arginine monohydrochloride) (e.g., + 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1);
  • aflibercept e.g., + 14 mg/ml
  • 20 mM histidine-based buffer e.g., + 2 mM
  • 5% (w/v) sucrose e.g., + 0.5%)
  • polysorbate 20 e.g., 0.02-0.04%)
  • the >8 mg VEGF receptor fusion protein when administered, is in an aqueous pharmaceutical formulation comprising: a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3 of VEGFR2, and a multimerizing component (e.g., which comprises amino acids 27-457 of SEQ ID NO: 2) at a concentration of at least about 100 mg/ml; about 5% sucrose; L-arginine (e.g., L-arginine monohydrochloride); a histidine-based buffer (e.g., containing histidine HCI); and about 0.03% surfactant; wherein the formulation has a pH of about 5.0 to about 6.8 (e.g., 5.8 to 6.5, for example 5.8).
  • a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3 of V
  • the formulation is suitable for intravitreal administration.
  • Other components that may be included are sodium sulfate, sodium thiocyanate, glycine, NaCI, sodium aspartate and/or sodium glutamate.
  • the VEGF receptor fusion protein is at a concentration of: about 100 mg/ml; about 111.5 mg/ml; about 112.0 mg/ml; about 113.3 mg/ml; about 114.3 mg/ml; about 115.6 mg/ml; about 116.3 mg/ml; about 120 mg/ml; about 133 mg/ml; about 140 mg/ml; about 150 mg/ml; about 200 mg/ml; or about 250 mg/ml.
  • the formulation may be characterized by (i) an osmolality of about 299 to about 506 mmol/Kg; and/or (ii) a viscosity of from about 6-15 cP at 20°C.
  • the surfactant may be a non-ionic surfactant such as polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350 or mixtures thereof.
  • the histidine-based buffer may be at a concentration of about 10 mM to 20 mM.
  • the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2- 8°C.
  • the >8 mg VEGF receptor fusion protein is, when administered in an aqueous pharmaceutical formulation, comprising: at least about 100 mg/ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3 of VEGFR2, and a multimerizing component (e.g., aflibercept); about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.
  • a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3
  • the aqueous pharmaceutical formulation includes:
  • VEGF receptor fusion protein e.g., aflibercept
  • histidine-based buffer e.g., aflibercept
  • L-arginine e.g., aflibercept
  • the >8 mg VEGF receptor fusion protein is, when administered in an aqueous pharmaceutical formulation comprising aflibercept at a concentration of at least about 100 mg/ml (e.g., about 111.5 mg/ml; 112.0 mg/ml; 113.3 mg/ml; about 114.3 mg/ml; about 115.6 mg/ml; or about 116.3 mg/ml); a thermal stabilizer which is a sugar, an amino acid, sucrose, mannitol, sorbitol, trehalose, L- proline, glycine, glycerol, taurine or propane sulfonic acid (e g., at about 2% (w/v) to about 10% (w/v), for example, 5% (w/v)); a buffer which is a histidine-based buffer, a phosphate-based buffer, an acetate-based buffer (e.g., at a concentration of about 5-25 mM, e.g.
  • the aflibercept is at a concentration in the aqueous pharmaceutical formulation of about 100 mg/ml; 101 mg/ml; 102 mg/ml; 103 mg/ml; 104 mg/ml; 105 mg/ml; 106 mg/ml; 107 mg/ml; 108 mg/ml; 109 mg/ml; 110 mg/ml; 111 mg/ml; 112 mg/ml;
  • the aqueous pharmaceutical formulation includes aflibercept at a concentration of at least about 100 mg/ml; sucrose, mannitol, sorbitol, trehalose; a histidine-based buffer; polysorbate 20 or polysorbate 80; and L-arginine, at a pH of about 5.0 to about 6.8; wherein the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.
  • the sucrose, mannitol, sorbitol or trehalose is at a concentration of about 2-10% (w/v); the L-arginine is at a concentration of about 10-100 mM; the polysorbate 20 or polysorbate 80 is at a concentration of about 0.02-0.1 % (w/v); and the histidine-based buffer is at a concentration of about 5-25 mM; at a pH of about 5.0 to about 6.8.
  • the present invention provides methods for treating angiogenic eye disorders (e.g., DR and/or DME) by sequentially administering initial loading doses (e.g., 2 mg or more, 4 mg or more or, preferably, about 8 mg or more of VEGF antagonist or inhibitor, for example, a VEGF receptor fusion protein such as aflibercept) (e.g., about every 2-4 or 3-5 weeks) followed by additional doses every 12-20 weeks, preferably 12-16 weeks, 12 weeks, 16 weeks or 20 weeks.
  • initial loading doses e.g., 2 mg or more, 4 mg or more or, preferably, about 8 mg or more of VEGF antagonist or inhibitor, for example, a VEGF receptor fusion protein such as aflibercept
  • the present invention provides methods for treating or preventing angiogenic eye disorders, such as diabetic macular edema (DME) and/or diabetic retinopathy (DR), by administering, sequentially, one or more (e.g., 3 or 4 or 5) doses of about 8 mg or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 2-4 or 3-5 weeks, e.g., every month (or about every 28 days, 28 + 5 days or about every 4 weeks), followed by one or more doses of about 8 mg or more VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) every 12 weeks (or about every 3 months or about every quarter year or about every 84 days) or every 16 weeks (or about every 4 months or about every 1/3 years or about every 112 days) or every 20 weeks.
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • the dosing regimen including the 12 week tertiary dosing interval may be referred to herein as a 12 week dosing regimen or 8q12 or HDq12; the dosing regimen including the 16 week tertiary dosing interval may be referred to herein as a 16 week dosing regimen or 8q16 or HDq16; and the dosing regimen including the 20 week tertiary dosing interval may be referred to herein as a 20 week dosing regimen or 8q20 or HDq20.
  • the present invention includes methods for treating angiogenic eye disorders (e.g., DR and/or DME) by administering, one or more times, >8 mg VEGF receptor fusion protein, preferably aflibercept, every 4 weeks, 8 weeks, 12-20 weeks, 12-16 weeks, 12 weeks or 16 weeks; as well as every 4 weeks for the first 3, 4 or 5 doses followed by dosing about every 8 weeks.
  • angiogenic eye disorders e.g., DR and/or DME
  • >8 mg VEGF receptor fusion protein preferably aflibercept
  • a subject begins receiving the >8 mg maintenance doses of every 12 or 16 or 20 weeks after the 8 mg monthly loading doses with no intervening doses.
  • the subject enters the maintenance dose phase rapidly/immediately after the loading dose phase.
  • the subject continues receiving the >8 mg 12 or 16 or 20 week doses without any intervening doses.
  • the subject does not receive a dosing regimen modification (DRM) or does not terminate treatment for at least 1 , 2, 3, 4 or 5 years.
  • DRM dosing regimen modification
  • the present invention also provides methods for improving visual acuity in subjects with type 1 or type 2 diabetes mellitus (e.g., subjects with diabetic macular edema or diabetic retinopathy), by administering, sequentially, one or more (e.g., 3 or 4 or 5) doses about every month (or about every 28 days, 28 + 5 days or about every 4 weeks), followed by one or more doses every 12 weeks (or about every 3 months or about every quarter year or about every 84 days) or every 16 weeks (or about every 4 months or about every 1/3 years or about every 112 days) or every 20 weeks.
  • the terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept).
  • the "initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”);
  • the “secondary doses” are the doses which are administered after the initial dose;
  • the “tertiary doses” are the doses which are administered after the secondary doses.
  • the initial, secondary, and tertiary doses may all contain the same amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), but will generally differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) contained in the initial, secondary and/or tertiary doses will vary from one another (e.g., adjusted up or down as appropriate) during the course of treatment.
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • a dosing regimen of the present invention may be expressed as follows: a method for treating an angiogenic eye disorder (e.g., DME or DR) in a subject in need thereof including administering (e.g., intravitreally) to the subject in need thereof, a single initial dose of about >8 mg (for example, in about 100 pl or less, about 75 pl or less or about 70 pl or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 p-l; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 pl;
  • a method for treating an angiogenic eye disorder e.g., DME or DR
  • administering e.g., intravitreally
  • a single initial dose for example, in about 100
  • VEGF antagonist e.g., a VEGF antagonist
  • VEGF receptor fusion protein such as aflibercept
  • secondary doses of the VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • tertiary doses of the VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • each secondary dose is administered 2 to 4 weeks (preferably, about 4 weeks) after the immediately preceding dose
  • each tertiary dose is administered 12 or 16 or 20 weeks (preferably, about 12-16, 12 or 16 or 20 weeks) after the immediately preceding dose.
  • the present invention includes methods wherein one or more additional, nonscheduled doses, in addition to any of the scheduled initial, secondary and/or tertiary doses of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) are administered to a subject.
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • Such doses are typically administered at the discretion of the treating physician depending on the particular needs of the subject.
  • the present invention also provides methods for treating angiogenic eye disorders (e.g., DR or DME) by administering to a subject in need thereof about >8 mg (for example, in about 100 pl or less, about 75 pl or less or about 70 tl or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl;
  • angiogenic eye disorders e.g., DR or DME
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • a pro re nata (PRN) treatment protocol calls for intervals between doctor visits to remain fixed (e.g., once every 2, 3, 4, 8, 12, 16 or 20 weeks) and decisions to carry out an injection of VEGF receptor fusion protein to be based on the anatomic findings at each respective visit.
  • a capped PRN dosing regimen is PRN wherein subjects must be treated at a certain minimal frequency, e.g., at least once every 2 or 3 or 4 months.
  • T&E Treatment & Extend
  • T&E regimens call for the time interval between doctor visits to be adjusted based on the patient’s clinical course — e.g., if a subject shows no sign of an active disease (e.g., the macula remains dry, without any leakage), the next one or more intervals can be extended; if there is fluid accumulation, the next interval will be shortened.
  • an injection of VEGF receptor fusion protein will be performed; the current clinical status only has an impact on the duration of the next injection interval.
  • the present invention includes embodiments wherein, at any point during a HDq12-20, HDq12, HDq16 or HDq20 treatment regimen, the patient can be switched to a PRN, capped PRN or T&E regimen.
  • the PRN, capped PRN and/or T&E may be continued indefinitely or can be stopped at any point and then the HDq12-20, HDq12, HDq16 or HDq20 regimen is reinitiated at any phase thereof.
  • Any HDq12-20, HDq12, HDq16 or HDq20 regimen can be preceded or followed by a period of PRN, capped PRN and/or T&E.
  • the present invention includes methods comprising administering the required doses of the HDq12 or HDq16 regimen, wherein each of the tertiary doses is administered 12 or 16 weeks after the immediately preceding dose, wherein the treatment interval between two tertiary doses is extended (e.g., from 12 weeks to 13, 14, 15, 16 or 20 weeks or from 16 weeks to 17, 18, 19, or 20 weeks), for example, until signs of disease activity or visual impairment deteriorate or recur and then either continuing dosing at the last tertiary interval used or the penultimate tertiary interval used.
  • the present invention includes methods comprising administering the required doses of the HDq12-20 or HDq12 or HDq16 or HDq20 regimen, wherein the treatment interval between any two tertiary doses is reduced (e.g., from 20 weeks to 19, 18, 17 or 16 weeks, from 16 weeks to 15, 14, 13, 12, 11 , 10, 9, 8, 7, 6, 5, 4, 3, or 2 weeks or from 12 weeks to 11 , 10, 9, 8, 7, 6, 5, 4, 3 or 2 weeks), for example, until signs of disease activity or visual impairment improve (e.g., BCVA stabilizes or improves and/or CRT stabilizes or reduces) whereupon, optionally, the interval between doses can be extended, e.g., back to a greater interval length.
  • the treatment interval between any two tertiary doses is reduced (e.g., from 20 weeks to 19, 18, 17 or 16 weeks, from 16 weeks to 15, 14, 13, 12, 11 , 10, 9, 8, 7, 6, 5, 4, 3, or 2 weeks or from 12 weeks to 11 , 10, 9, 8, 7, 6, 5, 4, 3 or 2 weeks), for example,
  • the interval between doses can be lengthened, for example by 4 week intervals as appropriate (e.g., from 12 weeks to 16 or 16 weeks to 20 weeks), for example if:
  • the subject receives the initial, secondary and, then, 12 or 16 week tertiary intervals and, then, after about 1 year, extending the tertiary intervals to about 20 weeks.
  • a method of treating an angiogenic eye disorder such as DR or DME as set forth herein includes the step of evaluating BCVA and/or CRT and lengthening the interval as discussed if one or both of the criteria are met.
  • the interval between doses e.g., during the 12-20 week or 12 week or 16 week or 20 week dosing phase
  • can be shortened e.g., from 12 or 16 or 20 weeks to 8 weeks; from 16 or 20 weeks to 12 weeks or from 20 weeks to 16 weeks, for example if:
  • BCVA EDRS or Snellen equivalent
  • a method of treating an angiogenic eye disorder such as DR or DME as set forth herein includes the step of evaluating BCVA and/or CRT and shortening the interval as discussed if one or both of the criteria are met.
  • the present invention also provides methods for treating angiogenic eye disorders (preferably, DME or DR) by administering: doses of about >8 mg (for example, in about 100 pl or less, about 75 pl or less or about 70 pil or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl;
  • doses of about >8 mg for example, in about 100 pl or less, about 75 pl or less or about 70 pil or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl;
  • VEGF antagonist e.g., a VEGF antagonist
  • VEGF receptor fusion protein such as aflibercept
  • secondary doses of the VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • tertiary doses of the VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • each secondary dose is administered 2 to 4 (preferably, 4) weeks after the immediately preceding dose
  • each tertiary dose is administered at about 4, 5, 6, 7 or 8 (e.g., 8) weeks after the immediately preceding dose; or about >8 mg (for example, in about 100 pl or less, about 75 pl or less or about 70 pl or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 p.
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • doses e.g., about 5 doses or 6 doses
  • about >8 mg for example, in about 100 pl or less, about 75 pl or less or about 70 pl or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl;
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • Dosing every “month” or after a “month” refers to dosing after about 28 days, about 4 weeks, or about 28 + 5 days and may encompass up to 5 weeks + 5 days. Dosing every “4 weeks” or after “4 weeks” refers to dosing after about 28 days (+ 5 days), about a month or about 28 (+ 5 days), and may encompass up to every 5 weeks (+ 5 days).
  • Dosing every “2-4 weeks” or after “2-4 weeks” refers to dosing after about 2 weeks (+ 5 days), 3 weeks (+ 5 days) or 4 weeks (+ 5 days). Dosing every “8 weeks” or after “8 weeks” refers to dosing after about 2 months (+ 5 days) or about 56 (+ 5 days).
  • Dosing every “12 weeks” or after “12 weeks” refers to dosing after about 3 months, about 84 days (+ 5 days), about 90 days (+ 5 days) or about 84 (+ 5 days). Dosing every “16 weeks” or after “16 weeks” refers to dosing after about 4 months or about 112 days (+ 5 days). [000198] Dosing every “12-20 weeks” or after “12-20 weeks” refers to dosing after 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks (+ 5 days), preferably about 12-16 weeks (+ 5 days), about 12 weeks (+ 5 days), about 16 weeks (+ 5 days) or about 20 weeks (+ 5 days).
  • Dosing every “12-20 weeks” refers to dosing after about 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks (+ 5 days), preferably about 12-16 weeks (+ 5 days), about 12 weeks (+ 5 days), about 16 weeks (+ 5 days) or about 20 weeks (+ 5 days).
  • a dose of > 8 mg encompasses a dose of about 8 mg or doses exceeding 8 mg, for example, about 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg.
  • Any dosing frequency specified herein may, in an embodiment of the invention, be expressed as the specific frequency “+ 5 days” (e.g., where “4 weeks” is stated, the present invention also includes embodiments such as 4 weeks + 5 days).
  • the term + 5 days includes ⁇ 1 , ⁇ 2, ⁇ 3, +4 and/or +5 days.
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • a predetermined interval e.g., hours, days, weeks or months
  • the present invention includes methods which comprise sequentially administering to the eye of a subject a single initial dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more secondary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more tertiary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept).
  • a VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • secondary doses of the VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • tertiary doses of the VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • An effective or therapeutically effective dose of VEGF antagonist for treating or preventing an angiogenic eye disorder refers to the amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) sufficient to alleviate one or more signs and/or symptoms of the disease or condition in the treated subject, whether by inducing the regression or elimination of such signs and/or symptoms or by inhibiting the progression of such signs and/or symptoms.
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • an effective or therapeutically effective dose of VEGF antagonist is about >8 mg every month, for 3 doses, followed by once every 12-20 weeks.
  • the alleviation of signs and/or symptoms is achievement, e.g., by 1 year, of a gain of >5, 10 or 15 letters BCVA (relative to baseline) (e.g., >5 letters improvement in a nAMD subject and/or 8-14 letters improvement in a DME patient/subject); achieving a BCVA > 69 letters; achieving no fluid at foveal center; reduction in central retinal thickness (CRT) by about 150 micrometers or more (e.g., below 300 micrometers in an nAMD subject/patient; and/or reduction by at least about 200 micrometers in a DR or RVO patient/subject) or achievement of normal CRT (e.g., about 300 micrometers or less); and/
  • Baseline values refer to values prior to initiation of a treatment (pre-dose).
  • angiogenic eye disorder means any disease of the eye which is caused by or associated with the growth or proliferation of blood vessels or by blood vessel leakage.
  • angiogenic eye disorders that are treatable or preventable using the methods of the present invention include:
  • nAMD age-related macular degeneration
  • ME macular edema
  • ME-RVO retinal vein occlusion
  • DME diabetic macular edema
  • CNV choroidal neovascularization
  • DR diabetic retinopathies
  • non-proliferative diabetic retinopathy e.g., characterized by a Diabetic Retinopathy Severity Scale (DRSS) level of about 47 or 53
  • proliferative diabetic retinopathy e.g., in a subject that does not suffer from DME
  • DRSS Diabetic Retinopathy Severity Scale
  • Diabetic retinopathy in a subject who has diabetic macular edema D E.
  • the present invention provides methods for treating angiogenic eye disorders (e.g., DR and/or DME) in a subject in need thereof, by sequentially administering initial loading doses (e.g., 2 mg or more, 4 mg or more or, preferably, about 8 mg or more of VEGF antagonist or inhibitor, for example, a VEGF receptor fusion protein such as aflibercept) (e.g., about every 2-4 or 3-5 weeks, preferably every 4 weeks; preferably, three initial loading doses) followed by additional doses every 12-20 weeks, preferably 12-16 weeks, 12 weeks, 16 weeks or 20 weeks wherein the subject achieves and/or maintains, e.g., by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96 weeks after treatment initiation:
  • initial loading doses e.g., 2 mg or more, 4 mg or more or, preferably, about 8 mg or more
  • DRSS Diabetic Retinopathy Severity Scale
  • CTR central retinal thickness
  • SD- OCT spectral domain optical coherence tomography
  • a subject receiving a HDq12 or HDq16 or HDq20 treatment for an angiogenic eye disorder e.g., DR and/or DME
  • an angiogenic eye disorder e.g., DR and/or DME
  • Do not receive a dose regimen modification e.g., wherein the interval between doses (e.g., tertiary doses) is reduced from the HDq12-20 or HDq12 or HDq16 or HDq20 treatment regimen once started, e.g., for at least 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96 weeks;
  • Non-inferior BVCA compared to that of aflibercept which is intravitreally dosed at 2 mg approximately every 4 weeks for the first 3, 4 or 5 injections followed by 2 mg approximately once every 8 weeks or once every 2 months; • Increase in BCVA (according to ETDRS letter score) of about 7, 8 or 9 letters by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96, e.g., wherein the baseline BCVA is about 61 , 62 and 63;
  • BVCA best corrected visual acuity
  • EDRS Early Treatment Diabetic Retinopathy Study
  • BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9, e.g., wherein the BCVA at any point between week 36 to 48 is about 60 or 70;
  • BCVA score (according to ETDRS letter score) from initiation of treatment of up to 38 letters when on the HDq12 or HDq16 regimen, e.g., wherein BCVA at baseline is between about 27 and 79;
  • a change in BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9; e.g., wherein the BCVA at any point between week 48 to 60 is about 69, 70, 71 , 72 or 73;
  • a BCVA improvement e.g., by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline BCVA is about ⁇ 73 ETDRS letters when on HDq12 regimen;
  • a BCVA improvement e.g., by week 48 following treatment initiation, of about 5 or 6 letters (ETDRS or Snellen equivalent) when baseline BCVA is about >73 ETDRS letters when on HDq12 regimen;
  • a BCVA improvement e.g., by week 48 following treatment initiation, of about 8 or 9 letters (ETDRS or Snellen equivalent) when baseline BCVA is about ⁇ 73 ETDRS letters when on HDq16 regimen;
  • a BCVA improvement e.g., by week 48 following treatment initiation, of about 4 or 5 letters (ETDRS or Snellen equivalent) when baseline BCVA is about >73 ETDRS letters when on HDq16 regimen;
  • a BCVA improvement e.g., by week 48 following treatment initiation, of about 7 or 8 letters (ETDRS or Snellen equivalent) when baseline CRT is ⁇ about 400 micrometers when on HDq12 regimen;
  • a BCVA improvement e.g., by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline CRT is >400 micrometers when on HDq12 regimen;
  • a BCVA improvement e.g., by week 48 following treatment initiation, of about 5 or 6 letters (ETDRS or Snellen equivalent) when baseline CRT is ⁇ about 400 micrometers when on HDq16 regimen;
  • a BCVA improvement e.g., by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline CRT is > about 400 micrometers when on HDq16 regimen;
  • BCVA does not lose 5, 10, 15 or 69 letters or more BCVA (e.g., after week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96 from start of treatment); • Between weeks 48 and 60, a BCVA score (according to ETDRS letter score) of about 69, 70, 71 , 72 or 73;
  • BCVA (according to ETDRS letter score) of at least about 69 letters, e.g., by week 48 or 60;
  • a BCVA between weeks 36 and 48 of about 71 , 72, 73 or 74 (ETDRS or Snellen equivalent) when on the HDq12 regimen e.g., when the basline BCVA is about 57, 58, 59, 60, 61 , 62, 63 or 64; or a BCVA between weeks 36 and 48 of about 69, 70, 71 , 72 or 73 (ETDRS or Snellen equivalent) when on the HDq16 regimen e.g., when the basline BCVA is about 55, 56, 57, 58, 59, 60, 61 , or 62;
  • a BCVA between weeks 48 and 60 of about 69 or 70 or up to 94 (ETDRS or Snellen equivalent) when on the HDq12 regimen e.g., when the basline BCVA is about 63 or 64; or a BCVA between weeks 48 and 60 of about 72 or 73 or up to 89 (ETDRS or Snellen equivalent) when on the HDq16 regimen e.g., when the basline BCVA is about 61 or 62;
  • DRSS Diabetic Retinopathy Severity Scale
  • DRSS diabetic retinopathy severity scale
  • Retina without fluid total fluid, intraretinal fluid [IRF] and/or subretinal fluid [SRF]
  • total fluid intraretinal fluid [IRF] and/or subretinal fluid [SRF]
  • SRF subretinal fluid
  • OCT optical coherence tomography
  • FA fluorescein angiography
  • SD-OCT spectral domain optical coherence tomography
  • Retina without fluid total fluid, intraretinal fluid [IRF] and/or subretinal fluid [SRF]) at the foveal center (e.g., by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment);
  • Dry retina e.g., by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96 from start of treatment;
  • Foveal center without fluid e.g., by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96 from start of treatment
  • OCT optical coherence tomography
  • CTR central retinal thickness
  • CTR central retinal thickness
  • Ocular e.g., intraocular pressure
  • non-ocular safety e.g., hypertensive events or APTC events
  • death rate in a subject suffering from an angiogenic eye disorder, e.g., DR or DME, similar to that of aflibercept which is intravitreal ly dosed at 2 mg approximately every 4 weeks for the first 3, 4 or 5 injections followed by 2 mg approximately once every 8 weeks or once every 2 months;
  • free aflibercept concentration in plasma of about 0.149 (+0.249) mg/l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • free aflibercept concentration in plasma of about 0.205 (+0.250) mg/l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • free aflibercept concentration in plasma of about 0.266 (+0.211) mg/l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • free aflibercept concentration in plasma of about 0.218 (+0.145) mg/l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • free aflibercept concentration in plasma of about 0.140 (+0.0741) mg/l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • free aflibercept concentration in plasma of about 0.0767 (+0.0436) mg/l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • free aflibercept concentration in plasma of about 0.0309 (+0.0241) mg/l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • free aflibercept concentration in plasma of about 0.0171 (+0.0171) mg/l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • free aflibercept concentration in plasma of about 0.00730 (+0.0113) mg/l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • adjusted bound aflibercept concentration in plasma of about 0.00698 (+0.0276) mg/l; e.g., wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • adjusted bound aflibercept concentration in plasma of about 0.00731 (+0.0279) mg/l; e.g., wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • adjusted bound aflibercept concentration in plasma of about 0.0678 (+0.0486) mg/l; e.g., wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • adjusted bound aflibercept concentration in plasma of about 0.138 (+0.0618) mg/l; e.g., wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • adjusted bound aflibercept concentration in plasma of about 0.259 (+0.126) mg/l; e.g., wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 7 days after the first dose, adjusted bound aflibercept concentration in plasma of about 0.346 (+0.151) mg/l; e.g., wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • adjusted bound aflibercept concentration in plasma of about 0.374 (+0.110) mg/l; e.g., wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • adjusted bound aflibercept concentration in plasma of about 0.343 (+0.128) mg/l; e.g., wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • adjusted bound aflibercept concentration in plasma of about 0.269 (+0.149) mg/l; e.g., wherein at baseline there is about 0.00583 mg/l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;
  • intravitreal VEGF inhibitor e.g., aflibercept
  • the maximum concentration of free aflibercept in the plasma is reached about 0.965 (e.g., about 1) day after the first dose;
  • C ma x Individual free aflibercept concentration (C ma x) in the plasma of from about 0 to about 1.08 mg/L (0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 or 1.1 mg/l);
  • Adjusted bound aflibercept concentration in the plasma of from about 0.137 to about 0.774 mg/L (0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 mg/l);
  • Efficacy and/or safety in a subject suffering from DR or DIME, similar to that of aflibercept which is intravitreally dosed at 2 mg approximately every 4 weeks for the first 5 injections followed by 2 mg approximately once every 8 weeks or once every 2 months, e.g., wherein efficacy is measured as increase in BCVA and/or reduction in central retinal thickness, e.g., wherein safety is as measured as the incidence of adverse events (treatment-emergent adverse events occurring anytime within 30 days of any injection) such as blood pressure increase, intraocular pressure increase, visual impairment, vitreous floaters, vitreous detachment, iris neovascularization and/or vitreous hemorrhage.
  • adverse events treatment-emergent adverse events occurring anytime within 30 days of any injection
  • the present invention provides the following:
  • a method for achieving a non-inferior BVCA compared to that of aflibercept which is intravitreally dosed at 2 mg approximately every 4 weeks for the first 3, 4 or 5 injections followed by 2 mg approximately once every 8 weeks or once every 2 months; in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the immediately preceding dose.
  • a single initial dose of about 8 mg or more of a VEGF receptor fusion
  • a method for achieving a BCVA (according to ETDRS letter score) of at least about 69 letters by week 48 or 60; in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the immediately preceding dose.
  • an angiogenic eye disorder preferably DR and/or DME
  • a single initial dose of about 8 mg or more of a VEGF receptor
  • BVCA best corrected visual acuity
  • a method for achieving between weeks 48 and 60 from treatment initiation, a BCVA score (according to ETDRS letter score) of about 69, 70, 71, 72 or 73; in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the immediately preceding dose.
  • a BCVA score according to ETDRS letter score
  • a change in BCVA score (accord
  • a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary dose
  • a method for achieving an gain at least 5, 10 or 15 letter by week 48 or 60 in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the immediately preceding dose.
  • a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed
  • EDRS or Snellen equivalent when on a HDq12 regimen
  • EDRS or Snellen equivalent when on a HDq12 regimen
  • a single initial dose of about 8 mg or more of a VEGF receptor fusion
  • a single initial dose of about 8 mg or more of a VEGF receptor
  • a single initial dose of about 8 mg or more of a VE
  • a single initial dose of about 8 mg or more of a VEGF receptor
  • EDRS or Snellen equivalent when on a HDq12 regimen
  • a single initial dose of about 8 mg or more
  • an angiogenic eye disorder preferably DR and/or D
  • an angiogenic eye disorder preferably DR and/or DME
  • VEGF receptor fusion protein vascular endothelial growth factor receptor fusion protein
  • a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) after the immediately preceding dose.
  • 69 letters when on the HDq16 regimen; in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) after the immediately preceding dose.
  • an angiogenic eye disorder preferably DR and/or DME
  • an angiogenic eye disorder preferably DR and/or DME
  • an angiogenic eye disorder preferably DR and/or DME
  • an angiogenic eye disorder preferably DR and/or DME
  • VEGF receptor fusion protein vascular endothelial growth factor receptor fusion protein
  • a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) after the immediately preceding dose.
  • 69 letters when on the HDq16 regimen; in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) after the immediately preceding dose.
  • an angiogenic eye disorder preferably DR and/or DME
  • an angiogenic eye disorder preferably DR and/or DME
  • EDRS angiogenic eye disorder
  • EDRS or Snellen equivalent angiogenic eye disorder
  • EDRS angiogenic eye disorder
  • EDRS angiogenic eye disorder
  • EDRS angiogenic eye disorder
  • EDRS angiogenic eye disorder
  • an angiogenic eye disorder preferably DR and/or DME
  • DRSS Diabetic Retinopathy Sever
  • DRSS diabetic retinopathy severity scale
  • a method for achieving a retina without fluid (total fluid, intraretinal fluid [IRF] and/or subretinal fluid [SRF]) at the foveal center and in center subfield by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment as measured by optical coherence tomography (OCT); in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen
  • FFA fluorescein angiography
  • a single initial dose of about 8 mg or more
  • SD-OCT spectral domain optical coherence tom
  • a method for achieving a retina without fluid (total fluid, intraretinal fluid [IRF] and/or subretinal fluid [SRF]) at the foveal center by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment); in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the immediately preceding dose.
  • a method for achieving a dry retina by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment; in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the immediately preceding dose.
  • an angiogenic eye disorder preferably DR and/or DME
  • OCT optical coherence tomography
  • a single initial dose of about 8
  • CTR central retinal thickness
  • OCT optical coher
  • an angiogenic eye disorder preferably DR and/or DME
  • a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one
  • a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or
  • an angiogenic eye disorder preferably DR and/
  • a method for achieving free aflibercept in the plasma maximum (mg/l) per dose (mg) of aflibercept of about 0.388 ( ⁇ 0.0328) mg/l/mg; in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or more tertiary doses of about 8 mg or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the immediately preceding dose.
  • a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary
  • an angiogenic eye disorder preferably DR and/or DME
  • a method for achieving a maximum level of about 0.387 mg/l ( ⁇ 0.135) adjusted bound aflibercept in the plasma; in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or more tertiary doses of about 8 mg or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the immediately preceding dose.
  • a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed
  • a method for achieving adjusted bound aflibercept in the plasma of from about 0.137 to about 0.774 mg/L; in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or more tertiary doses of about 8 mg or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the immediately preceding dose.
  • a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or more
  • a method for achieving adjusted bound aflibercept in the plasma maximum (mg/l) per dose (mg) of aflibercept of about 0.483 ( ⁇ 0.0168) mg/l/mg; in a subject in need thereof having an angiogenic eye disorder (preferably DR and/or DME) comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of aflibercept, followed by one or more secondary doses of about 8 mg or more of the aflibercept, followed by one or more tertiary doses of about 8 mg or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12- 20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the immediately preceding dose.
  • an angiogenic eye disorder preferably DR and/or DME
  • NKI-VFQ National Eye Institute Visual Function Questionnaire
  • a method for achieving a lack of macular edema by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment in a subject in need thereof having an angiogenic eye disorder comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the immediately preceding dose.
  • an angiogenic eye disorder preferably DR and/or DME
  • the molecular weight adjusted concentration of bound aflibercept (adjusted bound aflibercept) is calculated by multiplying the observed concentrations by 0.717 to account for the target VEGF weight in the complex in plasma in the concentration-time profiles discussed herein.
  • CRT and/or retinal fluid is as measured on spectral domain optical coherence tomography (SD-OCT).
  • SD-OCT spectral domain optical coherence tomography
  • a subject receiving a treatment for an angiogenic eye disorder e.g., diabetic macular edema (DME) and/or diabetic retinopathy (DR)
  • DME diabetic macular edema
  • DR diabetic retinopathy
  • Ocular serious TEAE e.g., through week 48 after treatment initiation
  • cataract subcapsular for example, cataract subcapsular, retinal detachment, ulcerative keratitis, vitreous haemorrhage or increased intraocular pressure, angle closure glaucoma, cataract, choroidal detachment, retinal detachment, retinal haemorrhage, skin laceration and/or vitreous haemorrhage
  • cataract subcapsular for example, cataract subcapsular, retinal detachment, ulcerative keratitis, vitreous haemorrhage or increased intraocular pressure
  • angle closure glaucoma cataract
  • choroidal detachment for example, cataract, choroidal detachment, retinal detachment, retinal haemorrhage, skin laceration and/or vitreous haemorrhage
  • cataract subcapsular for example, cataract subcapsular, retinal detachment, ulcerative keratitis, vitreous
  • TEAE intraocular inflammation e.g., through week 48 after treatment initiation
  • chorioretinitis e.g., chorioretinitis, iridocyclitis, LTDis, uveitis, vitreal cells and/or vitritis
  • Non-ocular serious TEAEs e.g., through week 48 after treatment initiation
  • acute left ventricular failure acute myocardial infarction, cardiac arrest, coronary artery disease, myocardial infarction, covid-19 pneumonia, gangrene, pneumonia, hyponatraemia, cerebrovascular accident, acute kidney injury, acute respiratory failure, angina pectoris, chest pain, cellulitis, pneumonia, pyelonephritis acute, urinary tract infection, upper limb fracture, hyponatraemia, osteoarthritis, bladder neoplasm and/or cerebrovascular accident;
  • T reatment emergent APTC event e.g., through week 48 after treatment initiation
  • non-fatal myocardial infarction e.g., through week 48 after treatment initiation
  • non-fatal stroke e.g., through week 48 after treatment initiation
  • vascular death e.g., through week 48 after treatment initiation
  • T reatment emergent hypertension events e.g., through week 48 after treatment initiation
  • blood pressure increased diastolic and/or systolic
  • hypertension diastolic hypertension
  • systolic hypertension hypertensive crisis
  • hypertensive emergency hypertensive urgency
  • labile hypertension labile hypertension and/or white coat hypertension
  • the present invention further includes methods for achieving a pharmacokinetic effect in a subject suffering from DR and/or DME comprising administering to an eye of the subject, at least one dose (e.g., a first dose) of about >8 mg VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept).
  • a pharmacokinetic effect can be one or more set forth below:
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • a VEGF receptor fusion protein such as aflibercept
  • 0.2-0.3 e.g., 0.310 or 0.245
  • free VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • aflibercept a VEGF receptor fusion protein such as aflibercept
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • aflibercept a VEGF receptor fusion protein such as aflibercept
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • aflibercept a VEGF receptor fusion protein
  • Reaches LLOQ of free VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • a clearance of the VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • the subject is administered: a single initial dose of about >8 mg or more of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more secondary doses of about >8 mg or more of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more tertiary doses of about >8 mg or more of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept); wherein each secondary dose is administered about 2 to 4 weeks (preferably, 4 weeks) after the immediately preceding dose; and wherein each tertiary dose is administered about 12-20 weeks (preferably, 12, 16 or 20 weeks) after the immediately preceding dose.
  • a VEGF antagonist e.g., a VEGF receptor fusion protein such as
  • the method for treating or preventing diabetic macular edema, in a subject in need thereof comprises administering >8 mg aflibercept (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by >8 mg aflibercept (0.07 mL) via intravitreal injection once every 8 - 16 weeks (2 - 4 months, +/- 7 days).
  • the method for treating or preventing diabetic retinopathy (DR), in a subject in need thereof comprises administering >8 mg aflibercept (0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days, monthly) for the first three doses, followed by >8 mg aflibercept (0.07 mL) via intravitreal injection once every 8 - 16 weeks (2 - 4 months, +/- 7 days).
  • the criteria are one or more of ocular infection, periocular infection; active intraocular inflammation; and/or hypersensitivity, e.g., to aflibercept or any component of a formulation thereof.
  • the method presented herein may include the step of evaluating the subject for such exclusion criteria and excluding the subject from said administration if any one or more if found in the subject; and proceeding with administration if exclusion criteria are not found.
  • a subject receiving VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • AEs adverse events
  • the AE can be treated in the subject and treatment can either be discontinued or continued.
  • the methods of present invention can include preparatory steps that include use of
  • the steps can include, for example: (1) visually inspecting the aqueous formulation in the vial and, if particulates, cloudiness, or discoloration are visible, then using another vial of aqueous formulation containing the aflibercept; (2) removing the protective plastic cap from the vial; and (3) cleaning the top of the vial with an alcohol wipe; then, using aseptic technique the following steps: (4) removing the 18-gauge x 134-inch, 5-micron, filter needle and the 1 mL syringe from their packaging; (5) attaching the filter needle to the syringe by twisting it onto the Luer lock syringe tip; (6) pushing the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or a bottom edge of the vial; (7) withdrawing all of the aqueous formulation in the vial and, if particulates, cloudiness, or discoloration are visible, then using another vial of aqueous formulation containing the
  • VEGF antagonist e.g., a VEGF receptor fusion protein such as aflibercept
  • injection of VEGF antagonist is performed under controlled aseptic conditions, which comprise surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) and anesthesia and a topical broadspectrum microbicide are administered prior to the injection.
  • controlled aseptic conditions comprise surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) and anesthesia and a topical broadspectrum microbicide are administered prior to the injection.
  • the present invention includes embodiments wherein a subject has a history of receiving one or more doses of aflibercept or any other VEGF antagonist (e.g., 2 mg aflibercept such as Eylea (e.g., 2q8 regimen) or one or more doses of about 8 mg aflibercept) and is then switched to a dosing regimen of the present invention, e.g., HDq12, HDq16, HDq20, HDq12-20 or HDq 16-20, starting at any step in the regimen.
  • aflibercept or any other VEGF antagonist e.g., 2 mg aflibercept such as Eylea (e.g., 2q8 regimen) or one or more doses of about 8 mg aflibercept
  • a dosing regimen of the present invention e.g., HDq12, HDq16, HDq20, HDq12-20 or HDq 16-20, starting at any step in the regimen.
  • a subject may have been initially administered aflibercept manufactured by a first process (a first aflibercept) and then is switched to aflibercept manufactured by a different process (e.g., a second aflibercept; e.g., a biosimilar aflibercept); for example, wherein each process is carried out by a different manufacturer.
  • a first aflibercept a first aflibercept
  • a different process e.g., a second aflibercept; e.g., a biosimilar aflibercept
  • Subjects may initially be receiving aflibercept according to a 2q8 dosing regimen comprising administering 5 initial monthly doses followed by one or more maintenance doses every 8 weeks (e.g., Eylea) and then switch to a HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen.
  • the aflibercept administered in the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen may have been manufactured by a different process, e.g., by a different manufacturer.
  • a subject may be receiving a HDq 12-20 or HDq 12 or HDq 16 or HDq20 dosing regimen with aflibercept and then switch to aflibercept manufactured by a different process, e.g., by a different manufacturer, while remaining on the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen.
  • the present invention encompasses, but is not limited to, methods for treating an angiogenic eye disorder, preferably DR and/or DME, wherein a subject is switched, from a first aflibercept (manufactured by one process) for use in a HDq12-20 or HDq12 or HDq16 or HDq20 regimen to a second aflibercept (manufactured by another process) for use in a HDq12-20 or HDq12 or HDq16 or HDq20 regimen.
  • a first aflibercept manufactured by one process
  • a second aflibercept manufactured by another process
  • the present invention includes embodiments wherein the subject initiates treatment of the second aflibercept HDq12-20 or HDq20 or HDq12 or HDq16 regimen at any dosing phase-initial, secondary or tertiary/maintenance — after having received the initial dose, one or more secondary doses or one or more tertiary/maintenance doses of the first aflibercept HDq12-20 or HDq20 or HDq12 or HDq16 regimen.
  • the present invention includes embodiments wherein, the subject is switched from any phase of the first HDq12-20 or HDq20 or HDq12 or HDq16 regimen into any phase of the second HDq12-20 or HDq20 or HDq12 or HDq16 regimen.
  • the subject will pick up receiving the second aflibercept HDq12-20 or HDq20 or HDq12 or HDq16 regimen at the dosing phase that corresponds to where dosing was stopped with the first HDq12-20 or HDq20 or HDq12 or HDq16 regimen, e.g., if a particular secondary dose was due with the first aflibercept therapy, the subject would timely receive the same secondary dose with the second aflibercept and, for example, continue receiving the second aflibercept according to the HDq12-20 or HDq20 or HDq12 or HDq16 regimen as needed thereafter.
  • the present invention also encompasses, but is not limited to, methods for treating an angiogenic eye disorder wherein a subject is switched, from a first aflibercept for use in a 2q8 regimen to a second aflibercept for use in a HDq12-20 or HDq20 or HDq12 or HDq16 regimen.
  • the present invention includes embodiments wherein the subject initiates treatment of the second aflibercept HDq 12-20 or HDq20 or HDq12 or HDq16 regimen at any dosing phaseinitial, secondary or tertiary/maintenance — after having received the initial dose, one or more secondary doses or one or more tertiary/maintenance doses of the first aflibercept 2q8 regimen.
  • the present invention includes embodiments wherein, for example, the subject is switched directly to the maintenance phase of the HDq12-20 or HDq20 or HDq12 or HDq16 regimen with second aflibercept after having received the initial and a single secondary dose in the 2q8 regimen with the first aflibercept.
  • a subject who has received an initial, one or more secondary doses and/or one or more tertiary doses of 2 mg aflibercept (e.g., Eylea) therapy (e.g., 2q8) according to the prescribed dosing regimen may receive an >8 mg dose of aflibercept, undergo an evaluation by a treating physician in about 8 or 10 or 12 weeks and, if, in the judgment of a treating physician, dosing every 12 weeks or every 16 weeks or every 20 weeks is appropriate (e.g., there is no undue loss in BCVA and/or increase in CRT), then continuing to dose the subject every 12-20 weeks, 12 weeks or 16 weeks or 20 weeks with >8 mg aflibercept.
  • 2 mg aflibercept e.g., Eylea
  • 2q8 mg aflibercept e.g., Eylea therapy
  • the present invention includes methods for treating or preventing an angiogenic eye disorder, preferably DR or DME, in a subject in need thereof, by administering to said subject >8 mg aflibercept, wherein:
  • the method comprises, after 1 month, administering to the subject the first >8 mg secondary dose of aflibercept and 1 month thereafter, administering the 2 nd >8 mg secondary dose of aflibercept; and then, every 12-20, 12 or 16 or 20 weeks thereafter, administering one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen; or
  • the method comprises, after another 1 month, administering to the subject the 2 nd >8 mg secondary dose of aflibercept; and then, every 12-20, 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen; or
  • the method comprises, after 12-20 or 12 or 16 or 20 weeks administering to the subject the 1 st >8 mg maintenance dose of aflibercept and all further >8 mg maintenance doses of aflibercept every 12-20 or 12 or 16 or 20 weeks according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen; or
  • the method comprises, after 12-20 or 12 or 16 or 20 weeks from the last maintenance dose of aflibercept, administering to the subject one or more >8 mg maintenance doses of aflibercept and all further >8 mg maintenance doses of aflibercept every 12-20 or 12 or 16 or 20 weeks according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen.
  • Patients may switch from a reference 2 mg aflibercept dosing regimen to a particular step in the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen.
  • a subject may receive only the initial 2mg dose of reference, and then, skipping the initial and secondary doses of the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen, begin receiving the HDq12-20 or HDq12 or HDq16 or HDq20 maintenance doses.
  • the present invention includes methods for treating or preventing DR and/or DME, in a subject in need thereof, by administering to said subject >8 mg aflibercept, wherein:
  • the method comprises, after 1 month, administering to the subject the initial >8 mg dose of aflibercept and, 1 month thereafter, the 1 st >8 mg secondary dose of aflibercept; and, 1 month thereafter, the 2 nd >8 mg secondary dose of aflibercept; and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the first >8 mg secondary dose of aflibercept and, 1 month thereafter, the 2 nd >8 mg secondary dose of aflibercept; and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12- 20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the 2 nd >8 mg secondary dose of aflibercept and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the 1 st >8 mg maintenance dose of aflibercept and all further >8 mg maintenance doses of aflibercept every 12-20 or 12 or 16 or 20 weeks according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after another 1 month, administering to the subject the initial >8 mg dose of aflibercept and, 1 month thereafter, the 1 st >8 mg secondary dose of aflibercept; and 1 month thereafter, the 2 nd >8 mg secondary dose of aflibercept; and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen; (6) the subject has received an initial 2 mg dose of aflibercept and a 1 st 2 mg secondary dose of aflibercept after 1 month, then the method comprises, after another 1 month, administering to the subject a first >8 mg secondary dose of aflibercept and, 1 month thereafter, the 2 nd >8 mg secondary dose of aflibercept; and then,
  • the method comprises, after another 1 month, administering to the subject the 2 nd >8 mg secondary dose of aflibercept and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12- 20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after another 1 month, administering to the subject the 1 st >8 mg maintenance dose of aflibercept and all further >8 mg maintenance doses of aflibercept every 12-20 or 12 or 16 or 20 weeks according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after another 1 month, administering to the subject the initial >8 mg dose of aflibercept and, 1 month thereafter, the 1 st >8 mg secondary dose of aflibercept; and 1 month thereafter, the 2 nd >8 mg secondary dose of aflibercept; and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after another 1 month, administering to the subject the first >8 mg secondary dose of aflibercept and, 1 month thereafter, the 2 nd >8 mg secondary dose of aflibercept; and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after another 1 month, administering to the subject the 2 nd >8 mg secondary dose of aflibercept and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 2 months, administering to the subject the 1 st >8 mg maintenance dose of aflibercept and, all further >8 mg maintenance doses of aflibercept every 12-20 or 12 or 16 or 20 weeks according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the initial >8 mg dose of aflibercept and 1 month thereafter, the 1 st >8 mg secondary dose of aflibercept; and 1 month thereafter, the 2 nd >8 mg secondary dose of aflibercept; and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the first >8 mg secondary dose of aflibercept and 1 month thereafter, the 2 nd >8 mg secondary dose of aflibercept; and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12- 20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 1 month, administering to the subject the 2 nd >8 mg secondary dose of aflibercept and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 2 months, administering to the subject the 1 st >8 mg maintenance dose of aflibercept and all further >8 mg maintenance doses of aflibercept every 12-20 or 12 or 16 or 20 weeks according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the subject has received an initial 2 mg dose of aflibercept and a 1 st 2 mg secondary dose of aflibercept after 1 month and a 2 nd 2 mg secondary dose of aflibercept after another 1 month and a 3 rd 2 mg secondary dose of aflibercept after 1 month; and a 4 th 2 mg secondary dose of aflibercept after 1 month; thereafter, then the method comprises, after 2 months, administering to the subject the initial >8 mg dose of aflibercept and, 1 month thereafter, the 1 st >8 mg secondary dose of aflibercept; and 1 month thereafter, the 2 nd >8 mg secondary dose of aflibercept; and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the subject has received an initial 2 mg dose of aflibercept and a 1 st 2 mg secondary dose of aflibercept after 1 month and a 2 nd 2 mg secondary dose of aflibercept after another 1 month and a 3 rd 2 mg secondary dose of aflibercept after 1 month; and a 4 th 2 mg secondary dose of aflibercept after 1 month; thereafter, then the method comprises, after 2 months, administering to the subject the first >8 mg secondary dose of aflibercept and, 1 month thereafter, the 2 nd >8 mg secondary dose of aflibercept; and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the subject has received an initial 2 mg dose of aflibercept and a 1 st 2 mg secondary dose of aflibercept after 1 month and a 2 nd 2 mg secondary dose of aflibercept after another 1 month and a 3 rd 2 mg secondary dose of aflibercept after 1 month, and a 4 th 2 mg secondary dose of aflibercept after 1 month; thereafter, then the method comprises, after 2 months, administering to the subject the 2 nd >8 mg secondary dose of aflibercept and, 12-20 or 12 or 16 or 20 weeks thereafter, one or more 12-20 or 12 or 16 or 20 weekly >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, after 2 months, administering to the subject the 1 st >8 mg maintenance dose of aflibercept and, all further >8 mg maintenance doses of aflibercept every 12-20 or 12 or 16 or 20 weeks according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen; (21) the subject has received an initial 2 mg dose of aflibercept and a 1 st 2 mg secondary dose of aflibercept after 1 month and a 2 nd 2 mg secondary dose of aflibercept after another 1 month and a 3 rd 2 mg secondary dose of aflibercept after
  • the subject has received an initial 2 mg dose of aflibercept and a 1 st 2 mg secondary dose of aflibercept after 1 month and a 2 nd 2 mg secondary dose of aflibercept after another 1 month and a 3 rd 2 mg secondary dose of aflibercept after 1 month; and a 4 th 2 mg secondary dose of aflibercept after 1 month; and one or more 2 mg maintenance doses every 8 weeks thereafter, then the method comprises, 2 months after the last aflibercept maintenance dose administering to the subject the first >8 mg secondary dose of aflibercept and, 1 month thereafter, the 2 nd >8 mg secondary dose of aflibercept; and then, every 12-20 or 12 or 16 or 20 weeks thereafter, one or more >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen;
  • the method comprises, 2 months after the last aflibercept maintenance dose, administering to the subject the 2 nd >8 mg secondary dose of aflibercept and, 12-20 or 12 or 16 or 20 weeks thereafter, one or more 12-20 or 12 or 16 or 20 weekly >8 mg maintenance doses of aflibercept according to the HDq12-20 or HDq12 or HDq16 or HDq20 dosing regimen; or

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Abstract

La présente invention concerne des régimes pour le traitement de troubles oculaires angiogéniques tels que DR et DME caractérisés par des doses élevées d'aflibercept et des intervalles d'allongement entre des doses.
PCT/US2023/015223 2022-03-15 2023-03-14 Régimes d'antagoniste de vegf à dose élevée et étendu pour le traitement de troubles oculaires angiogéniques WO2023177689A1 (fr)

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